Is this the smoking gun to Melanoma and the reoccurrence the plasticity of the Macrophages?..Jim Breitfeller

Is this the smoking gun to Melanoma and the reoccurrence the plasticity of the Macrophages? The (TAM) Tumor Associated Macrophage or more precisely M2-Like Phenotype.
In my search for answers, I have been focusing in on how the tumor escapes detection by the immune system. We need to know what is going on in vivo during the different stages of melanoma.

The tumor mass is undoubtedly a multifaceted show, where different cell types, including neoplastic cells, fibroblasts, endothelial, and immune-competent cells, interact with one another continuously. Macrophages represent up to 50% of the tumor mass, and they certainly operate as fundamental actors. Macrophages constitute an extremely heterogeneous population; they originate from blood monocytes, which differentiate into distinct macrophage types, schematically identified as M1 (or classically activated) and M2 (or alternatively activated).

It is now generally accepted that TAMs have an M2 phenotype and show mostly pro-tumoral functions, promoting tumor cell survival, proliferation, and dissemination. High levels of TAM are often, although not always, correlated with a bad prognosis, and recent studies have also highlighted a link between their abundance and the process of metastasis.

In a recent research paper “Immunotype and Immunohistologic Characteristics of Tumor Infiltrating Immune Cells are Associated with Clinical Outcome in Metastatic Melanoma”1 et al Slingluff 2012, it breaks down the Immunohistologic Characteristics into three distinct immunotypes:

A) No infiltration of immune cells in the tumor’s microenvironment.

B) Infiltrating Immune cells only in close proximity to the tumor’s vascular system

C) Diffuse immune cell infiltrates throughout a metastatic tumor and its microenvironment.

Immunohistologic Characteristics of Tumor Infiltrating Immune Cells


Overall, the most predominant immune cells were T cells (53%), followed by the B cell lineage cells (33%), and then by macrophages (13%), with NK and mature dendritic cells only hardly present.

With the setting of the tumor’s microenvironment evaluated, we will focus the low survival immunotype A patients.

How can we improve the overall survival and the immune response to Melanoma? We need to push the differentiation of the macrophages towards the M1 phenotype.

Macrophages are important tumor-infiltrating cells and play pivotal roles in tumor growth and metastasis. Macrophages participate in immune responses to tumors in a polarized manner: classic M1 macrophages produce interleukin (IL) 12 to promote tumoricidal responses, whereas M2 macrophages and M2-Like produce IL10 and help tumor progression. The mechanisms governing macrophage polarization are unclear but in 1990 it was discovered treatment of M2 macrophages with GM-CSF or IFN-gamma led to production of M1 phenotypic markers upon LPS stimulation. It also has been seen that if you block the IL-10 receptor with an antibody along with LPS (TLR4 agonist) stimulation or CpG (TLR9 agonist) stimulation you shift the Macrophage plasticity towards the M1 phenotype.

So what causes the high Macrophage (M2) to migrate towards the Tumor and its microenvironment? Does the tumor somehow recruit these (TAMs) Tumor Associated Macrophages? What are the characteristics of the M2 phenotype?

Hallmarks of M2 macrophages are IL-10high IL-12low IL-1rahigh IL-1 decoyRhigh production, CCL17 and CCL22 secretion, high expression of mannose, scavenger and galactose-type receptors, poor antigen-presenting capability and wound-healing promotion.

CCL17 and CCL22 chemokines within tumor microenvironment are related to infiltration of regulatory T cells in Macrophage 2 in melanoma. Early Detection of Tumor Cells by Innate Immune Cells leads to Treg Recruitment through CCL22 Production by Tumor Cells and Tumor Assocated Marophages (TAMs). It has been suggested that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits Treg to evade this early antitumor immune response. The activated T-cells upregulate the CTLA-4 and PD-1. PD-1 ligation induces IL-10 production by monocytes, which together with PD-1 inhibits CD4+ T cell responses/activation. This is way for the immune system to use a checkpoint so that immune response does not lead to an autoimmune response. These receptors keeps the immune system in check.

Now in another paper I found this:


If you look at the above micrographs, you will see that the two patients that had relapsed (10710 and 10737) had IL-1b and IL-6 and TNF alpha missing. The macrophages were not activated!!!! The "Danger Signal" known as inflammation was missing! The non-responders most likely had their macrophages polarized to a M2-like phenotype by the Tregs and or IL-10.



So if the Macrophages are M2-like in the Tumor’s microenviroment, then if we control the Tregs, the upregulation of the of CTLA-4, PD-1 on the T-cells including the Tregs, and control the IL-10 production through anti-IL-10 antibody on the macrophages, we can shift the M2-like Macrophages into the M1 thus producing IL-12 shifting the differentiation of the Niave CD4+ T-cell the TH1 phenotype to activate the T-cells.


This all can be done with Yervor, Anti-PD-1 and Anti-IL-10 receptor antibody. You can get the tomor to shed antigentic protein by either whole radiation, Chemotherapy (TMZ- + Patrin-2) or Heat Shock.


CpG oligonucleotides induced NF-_B activation through the triggering of TLR9 signaling in TAM (Fig. 2), and the co-use of an IL-10 receptor Ab reduced IL-10 signaling in TAM, thereby reducing their M2 polarization.



Plasticity of Macrophage Function during Tumor Progression: Regulation by Distinct Molecular Mechanisms
Source: http://www.jimmunol.org/content/180/4/2011.full.pdf

HMGB1 from the dying tumors (irradiation, Chemotherapy, Heat Shock) will act as the Danger signal and bind to the TLR4 and activating the Macrophage (M1) and secrete IL-12 which acts upon the naïve CD4 T helper cells to differentiate to the Th1 phenotype.



petoh et al. has revealed an interesting role of TLR signalling in cancer therapy. They studied the immune-stimulatory properties of dying tumour cells after chemotherapy or radiation therapy. Using TLR4 and MyD88-deficient DCs, they show that TLR4 signaling is required for crosspresentation of antigens from apoptotic tumour cells on MHC class I to generate antitumour cytotoxic T cell (CTL) responses. Apetoh et al.also identified a “danger signal” from dying tumour cells, the nuclear protein highmobility group box 1 protein (HMGB1, see Figure) that triggers this protective immune response through activation of TLR4. According to their work, the interaction of high mobility group box 1 protein (HMGB1) released from dying tumour cells with Toll-like receptor 4 (TLR4) on dendritic cells is required for the crosspresentation of tumour antigens and the promotion of tumour specific cytotoxic T-cell responses.

So to sum it up, If you take Yervoy + Anti-PD1 + Anti-IL-10 along with radiation/Chemo could we get the right T-cell activation and Immune Response?

My guess you will activate the TLR4 pathway and induce the RIGHT IMMUNE RESPONSE.




So can we Get the Oncologists on board to propose and setup a clinical trial?
Time will only tell.
Remember the this blog. It will lead to a CURE!!!


“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

'Pep talk' can revive exhausted immune cells: Study..Melanoma..Jim Breitfeller

'Pep talk' can revive exhausted immune cells: Study
Published: Wednesday, Dec 14, 2011, 14:33 IST
Place: Washington, DC | Agency: IANS

'Pep talk' can revive exhausted immune cells



Exhaused immune cells can be revived by blocking the receptors PD-1 on the The CD8+ T-cells. By reviving the immune cells (CD8+), one can jump start the immune system and may be able to recognize the Melanoma tumors. There are now a number of clinical trials with this therapy in mind.




“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Identifying and Over Coming Immune Barriers at the Level of the Tumor Microenvironment..Melanoma .Jim Breitfeller

Eleventh International Conference on Progress in Vaccination Against Cancer

Dr. Thomas Gajewski
University of Chicago,Chicago,IL,USA

"Immunotherapeutic approaches for the treatment of melanoma, such as tumor antigen-based vaccines, can frequently boost immune responses. However, clinical responses as measured by tumor shrinkage are seen in only a minority of patients. This observation has prompted careful analysis of the tumor microenvironment for biologic correlates to clinical response and also to identify mechanisms of tumor resistance. Patients with advanced melanoma treated with antigen-specific vaccines had pre-treatment tumor biopsies analyzed by gene expression profiling. Supervised hierarchical clustering was performed based on clinical outcome. An expanded bank of tumors was analyzed to increase the sample size and better understand gene patterns.
Two major categories of melanoma metastases have been observed.

One subgroup of patient has an inflamed phenotype that includes expression of chemokines, T-cell markers, and other immunoregulatory factors. Clinical responders to melanoma vaccines appear to fall within this subset. This group also contains the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3, suggesting that these immunosuppressive mechanisms may dominantly inhibit anti-tumor –cell function in those patients. In addition, absence of B7 expression supports classical T-cell anergy. Preclinical experiments have confirmed a critical role for these mechanisms in limiting anti-tumor T–cell efficacy in vivo, giving candidate treatment strategies for translation back into the clinic.

A second subset of patients is represented by tumors which are non-inflamed and lack chemokines for T cell recruitment. Therefore, a major barrier in these cases appears to be failed T –cell migration into tumor sites. Experimental strategies to augment T-cell migration can have important anti-tumor effects in preclinical models. The presence of the "inflamed" gene signature was associated with a type I IFN transcriptional profile, and murine experimental models have confirmed a critical role for type I IFN signaling in promoting adaptive immunity."


So,In the first subset, tumors had a suppresive nature that may be over riddden by Anti-CTLA-4 (Yervoy) and or Anti-PD-1 Therapy

The second subset was missing the "danger signal" inflammatory cytokines and chemoattractants most likely due to STAT3 signaling from the Tumor.

Stimulation of Toll-like receptor 4 (TLR-4) activates macrophages and results in the release of TNF-alpha. It is hypothesized that melanoma inhibits macrophage activation by suppressing TLR-4 signaling.








Cytokines are small proteins which allow cells of the immune system to communicate with one another via cytokine receptors expressed at the cell surface.
Activated macrophages defend against tumors by secreting cytokines to recruit secondary immune cells, presenting antigen to T cells, and by direct tumor cytotoxicity. Peritoneal macrophages harvested from melanoma-bearing mice are less cytotoxic to melanoma cells, and produce less superoxide, nitric oxide, and tumor necrosis factor-alpha (TNF-alpha) than those from nontumor-bearing mice. Similar impairment of macrophage activation occurs in vitro using media harvested from cultured melanoma cells.

Activated Macrophages secrete the following cytokines under different conditions:
IL-1,IL-12,IL-6, IFN-gamma/alpha/beta and TNF-alpha


IL-6


Interleukin 6 is a pro-inflammatory cytokine and is produced in response to infection and tissue injury. IL-6 exerts its effects on multiple cell types and can act systemically.

IL-6 stimulates liver secretion of acute phase proteins
IL-6 stimulates B-lymphocytes to produce antibodies
IL-6 in concert with IL-1b causes T-cell activation
IL-6 induces STAT 3 Signaling
IL-6 Plus TGF-b induces the Th17 cell phenotype


IL-1 beta

Interleukin-1b is a pro-inflammatory cytokine which is secreted by macrophages activated by a number of stimuli including TNF-alpha, bacterial endotoxin and IL-1b itself.
IL-1b exerts its effects on many different cell types locally at the site of production and systemically (at a distance).


IL-12


Interleukin-12 is a heterodimer consisting of a p35 and a p40 subunit. Both subunits are required for receptor binding and biological activity.
IL-12 stimulates growth of activated Natural Killer (NK) cells, CD8+ and CD4+ T- cells.
IL-12 increases NK and T-cell g-IFN production which shifts T-cell differentiation towards a Th1-type response.
IL-12 increases NK production of TNF-alpha which can act synergistically with IFN-gamma.
IL-12 suppresses IL-4 induced IgE production.


TNF-alpha


Tumor Necrosis Factor alpha is made by many other cells as well as macrophages, which are major sources, especially after priming by Interferon gamma.
TNF-alpha initiates a cascade of cytokines which mediate an inflammatory response. TNF-alpha effects are mediated through two types of receptor, a 75kDa TNFR-a receptor and a 55kDa TNFR-b receptor.
TNF-alpha regulates the expression of many genes in many cell types important for the host response to infection.

IFN-gamma/beta

Macrophages, and many other cells produce these Type I interferons which act as immunomodulatory, as well as antiviral cytokines. Distinct receptor from interferon gamma, mediates overlapping or competing effects on macrophages. Cellular signalling pathways involve Jak/Stats, and other pathways.

So, if Melanoma suppresses Macrophage Activation, then the tumor microenviroment is missing IL-6, IL-1b and other cytokines.

If you look at the above micrographs, you will see that the two patients that had relapsed (10710 and 10737) Had IL-1b and IL-6 missing. The macrophages were not activated!!!! The "Danger Signal" known as inflammation was missing!





The missing combination of IL-1 and IL-6 meant there is no T-cell activation. And no induction of the Th17 phenotype. It is now becoming a lot more clearer based on Dr. Gajewski's findings.


Now might be the time for a critical re-evaluation of our overall approaches to targeting STAT3 and for developing new models for disrupting the protein in order to accomplish the goal of delivering clinically useful direct STAT3 inhibitors as novel anticancer agents in a timely manner.






“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

MedImmune Inks Deal for Pfizer's Anticancer mAb Therapeutic..Melanoma .Jim Breitfeller

MedImmune inked an in-license agreement with Pfizer for tremelimumab, a mAb therapeutic for various types of cancer. Pfizer presented final toxicity results of a Phase I dose-escalation trial of tremelimumab in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer.

Under terms of the deal MedImmune will assume global development rights to tremelimumab. Pfizer retains rights to use the drug compound with specified types of combination therapies.

Pfizer previously signed over developments rights covering tremelimumab in melanoma to Debiopharm after the mAb failed in a Phase III melanoma trial. The interim analysis found that it would not offer any benefit over standard chemotherapy. Thus in April 2008, Pfizer was forced to halt the trial.

A full evaluation of the data revealed a biomarker that predicted patients who were more likely to respond, according to Pfizer. Debiopharm will be responsible for conducting a new Phase III study that leverages this marker to select patients with unresectable, stage IV melanoma. At the time of inking the deal with Debiopharm, Pfizer said it would retain all commercial rights.

Tremelimumab is a fully human mAb that binds to the protein CTLA-4, expressed on the surface of activated T lymphocytes. "Adding another immunotherapeutic approach to our oncology pipeline, one which may employ the immune system itself to fight cancer, exemplifies our continued commitment to embracing this new era of cancer care," says Bahija Jallal, Ph.D., MedImmune's evp, R&D.

MedImmune has seven clinical-stage mAb programs for cancer treatment. Phase I candidates bind to CEA and CD3, CD22, IGF, CD19, and Ang2. The Phase II candidate targets PDGFRα and is being tested in lung cancer and glioblastoma. The company believes that the platelet-derived growth factor receptor alpha (PDGFRα) pathway, with its potential role in regulating transformation as well as tumor microenvironment, progression, and metastasis, may be an important cancer target.

MEDI-575 is a fully human mAb to PDGFRα being tested in lung cancer. It has been shown to inhibit signaling from PDGFRα on cancer cells and supportive stroma. However, MEDI-575 reportedly does not inhibit PDGFRβ, the inhibition of which has been associated with significant clinical toxicities including extravascular fluid accumulation.

MEDI-575 is a fully human mAb to PDGFRα being evaluated as a treatment for glioblastoma multiforme. MEDI-575 has been shown to inhibit signaling from PDGFRα on cancer cells and supportive stroma but not PDGFRβ, MedImmune says


Bristol Myer Squibb will now be looking in the rearview mirror and seeing MedImmune in it. Down the road we may see the price of these anti-CTLA-4 antibodies go down.


Also MedImmune has an US Patent Application 20100028330 - METHODS OF UPMODULATING ADAPTIVE IMMUNE RESPONSE USING ANTI-PD1 ANTIBODIES.

This is becomming Very Intersesting!!!

A race for the CURE!!!!!




It is good to see some Competition.



“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

The Anti-PD-1 Therapy Race for Approval by the FDA is On..Melanoma ..Jim Breitfeller

When it rains, it pours!!!! Melanoma patients over the last twenty years have not seen any progress in the fight to cure Melanoma. That has all changed in 2011 when the FDA approved Yervoy (Ipi..Ipilimumab), an anti-CTLA-4 monoclonal antibody and Zelboraf (vemurafenib). Well, this all going to change Melanoma from a cancer to a chronic disease that may be stabilized or even cured. The new Kid on the block( PD-1) is another Surface molecule that is unregulated when the T-cells are activated. This molecule is time dependent , which means that over time it migrates to the surface. Base on the research today, PD-1 molecule causes global inhibition to activated T-cells and down regulates the IL-2 expression by the PI3K/Akt pathway. It also inhibits the ICOS molecule that is an important co-stimulator for the T-cells.




So with stakes high to be the first to market, Bristol Myer Squibb, a little known company, Amplimmune, co-sponsored by GlaxoSmithKline and Curetech, a subsidiary of Teva Pharma of Israel are in the race of their lives. Winner takes all. And to throw Icing on the cake, the blockage of both inhibitors (PD-1 and CTLA-4) have shown remarkable ability to eradicate Melanoma tumors in mice.



Bristol Myer Squibb seems to be leading this race with a clinical trials recruiting at Sloan Kettering in New York and Yale in Connecticut.

The study is “Dose-escalation Study of Combination BMS-936558 (MDX-1106) and Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma”
Trial: NCT01024231

So with this in mind, if was seeking to try a clinical trial at this time, I would seek out the combination first, then PD-1 and if all else fails, Anti-CTLA-4 therapy followed by IL-2.

I see a Stabilization/Cure on the horizon for this disease and others based on these immunotherapies.



“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Why Is Interleukin-2 so important for mounting an immune response?.Melanoma..Jim Breitfeller

The T-cell-specific cell-surface receptors CD28, CTLA-4, ICOS and PD-1 are important regulators of the immune system. CD28 potently enhances those T-cell functions that are essential for an effective antigen-specific immune response, and the homologous CTLA-4 counterbalances the CD28-mediated signals and thus prevents an otherwise fatal overstimulation of the lymphoid system. PD-1 engagement can prevent ICOS but not CD28 costimulation. The inability of ICOS costimulation to override PD-1 inhibition is directly related to the low IL-2 levels it induces upon its engagement. ICOS Costimulation requires IL-2 and can be prevented by CTLA-4, PD-1 engagement. With the CD3/CD28 blocked downstream at the P13K and the Akt pathways, the T-cell is activated but the proliferation and survival of T-cells/immune response is terminated.



A picture is worth a thousand words.






Based on the above model, Downstream of the CD3/CD28 signaling the co-inhibitors down modulate the P13/Akt signaling. Signaling via CD28 is required for optimum IL-2 production, cell cycle progression, and survival. CD28 is constitutively expressed on naive CD4+ T cells is slightly upregulated after T cell activation.







The CTLA-4 and the PD-1 expression increase over time in Melanoma patients. This is why it is so very hard to eradicate Melanoma in the late stage IV.


To counteract the inhibition, one can use Antibodies to block the suppressive signaling coming from the CTLA-4 and PD-1. This is where Yervoy (Anti-CTLA-4) and Anti-PD-1 come into play. So if you can do a therapy with a systematic approach, you may be able to beat Melanoma.
It is now known, that IL-2 can down regulate PD-1 receptor so you might not need to do Anti-PD-1 therapy. Or you might do anti-PD-1 instead of IL-2 therapy to cut down the harsh effects of the IL-2 therapy. It is now known that the T-cell activation/immune response needs IL-2 to produce a robust immune response.






“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Ultimate fate of cellular immune responses is determined by the balance between positive & negative signals delivered by T-cells..Melanoma ..Jim Breit

ICOS Expression,To secrete and what to secrete is the question.







My research has taken me to the costimulators and coinhibitors of the T-cell activation. The Delicate balance between the costimulators and coinhibitors render the right immune response at the right time. One of these costimulators is the ICOS. But if there is to much ICOS, then there is a down regulation of the the immune response by the secetion of IL-10 into the tumor's microenviroment.

The level of ICOS surface expression regulates the magnitude of the in vivo Th1/Th2 ratio, perhaps by influencing Th2 differentiation. This regulation plays a major role in the differentiation of the T-cells.


The linkage between low ICOS expression and “early” cytokines, and between intermediate/high ICOS expression and “late” cytokines is intriguing and could mean that ICOS is gradually up-regulated in the course of progressing T cell differentiation.

ICOS-low-cells were found to be loosely associated with the early cytokines interleukin (IL)-2, IL-3, IL-6, and interferon (IFN)-gamma.

ICOS-medium cells, the large majority of ICOS_ T cells in vivo, were very tightly associated with the synthesis of the T-helper type 2 (Th2) cytokines IL-4, IL-5, and IL-13, and these cells exhibited potent inflammatoryeffects in vivo.

In contrast, ICOS-highT cells were highly and selectively linked to the antiinflammatory cytokine IL-10.

The strength of the effector response of Th cells is regulated by the control of ICOS expression.

Overall, this data seem to indicate that ICOS cell surface density serves as a regulatory mechanism for the release of cytokines with different immunological properties.

We want the low expression of ICOS which seems to differeniate the niave T-cells towards the TH1 T-cell phenotype. We can accomplish that with Yervoy (Anti-CTLA-4). STAT5 signaling is found in both the Th2 and Treg pathway.It just so happens Yervoy causes the phosphorylation of STAT5 to decreased significantly with increasing concentrations . Yervoy skews the T-cell differentiation towards the Th1/Th17 phenotype which we want.

Another coinhibitor which surpresses the immune resonse is (PD-1) Program Death 1.

Blockade of PD-1 by monoclonal antibodies specific to its ligands (PD-L1 and PD-L2) results in significant enhancement of proliferation and cytokine (gamma interferon [IFN-gamma] and interleukin-2 [IL-2]) secretion by tumor-specific CTLs. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Tregs.

So by do a combinatorial therapy with Yervoy and PD-1 antibodies, It would most likely have a synergistic immune response.



This why on 9-20-2011, Bristol Myer Squibb expanded it's deal with Japan's Ono Pharmaceutical Co. Ltd. BMS now knows that they have an monopoly on T-cell activation and can be applied to many other cancers besides Melanoma. They are collecting the "String of Pearls". It would not surprise me they will go after the rest of the costimulators and coinhibitors on the T-cells. Only time will tell.

My hope is that Bristol Meyer Squibb uses it for the cure of cancer one day and not just monetary gains.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

“Schedule and Dose for Combination Therapy,” Melanoma.. 2011 Scientific Colloquium of the Cancer Immunotherapy

“Schedule and Dose for Combination Therapy,”
2011 Scientific Colloquium of the Cancer Immunotherapy Consortium
• Thursday, March 17, 2011 7:00 AM - Saturday, March 19, 2011 1:30 PM
Eastern Time


First Speaker: Dr. Rafi Ahmed
Director of the Emory Vaccine Center

"As a basic immunologist, EVC Director Dr. Rafi Ahmed studies immunological memory – the ability of the immune system to “remember” a particular antigen and respond accordingly. Dr. Ahmed and his colleagues have made significant discoveries about how immune memory cells are created and how long they survive; understanding these mechanisms is crucial to the development of vaccines for HIV and other infectious agents. In addition to contributing vitally to vaccine science, Dr. Ahmed’s findings are being applied to research into therapies for the treatment of cancer and the prevention of organ rejection."




Dr. Rafi Ahmed is now being introduced by Johannes Vieweg, & highlighting his work on immunological memory

Dr. Ahmed is sharing how lessons from immune memory development in chronic viral infection can inform cancer immunotherapy field

Ahmed: wait 30-60 days to boost in vaccination produces better immune responses for many types of viral vaccines. Same for cancer?JimmyB :Why 30 to 60 days? Because this is the time factor that it takes for the CD4+ and CD8+ T-cells to grow and differentiate into effector T-cells. (See Graph)




Fig-1

Dr. Rafi Ahmed is now being introduced by Johannes Vieweg, & highlighting his work on immunological memory Dr. Ahmed is sharing how lessons from immune memory development in chronic viral infection can inform cancer immunotherapy field Ahmed: wait 30-60 days to boost in vaccination produces better immune responses for many types of viral vaccines. Same for cancer?
Fig-2

Ahmed: Synergy we've seen combining PD-1 with IL-2 (negative + positive signal) in viral infection therapy have been astonishing.

Jimmy B:Imagine if you combine CTLA-4 + PD-1 and IL-2. The Holy Grail of Immuno therapy I believe.Ahmed raises point that mTOR inhibition may enhance vaccine-induced memory CD8 T-cells. Role for combining with cancer vaccines?

Much audience Q&A for Dr. Ahmed - when see exhaustion clinically, is it inhibition, effect of dose of IL-2, and role of autophagy?

Source: Cancer Research on Twitter

http://twitter.com/#!/search?q=%23cic11












“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,

Jimmy B

MSKCC to Test Agenus' Personalized Cancer Vaccine in Combination With Novel Immunomodulatory Agents Melanoma..Jim Breitfeller

MSKCC to Test Agenus' Personalized Cancer Vaccine in Combination With Novel Immunomodulatory Agents

LEXINGTON, Mass., Jan. 24, 2011 (GLOBE NEWSWIRE) -- Agenus Inc. (Nasdaq:AGEN) today announced it has entered into a research agreement with Memorial Sloan-Kettering Cancer Center (MSKCC) using Agenus' proprietary cancer vaccine technology.

The collaboration will test Agenus' cancer vaccine in combination with antibodies that are intended to target specific markers on tumor cells, such as CTLA-4 and PDL-1. This group of antibodies represents a new class of immunotherapeutic agents that are thought to have complementary mechanisms of action with cancer vaccines. The studies will be performed in the laboratory of Jedd D. Wolchok, M.D., Ph.D., a leader in the field of cancer immunotherapy. Dr. Wolchok serves as the Associate Director of the Ludwig Center for Cancer Immunotherapy at MSKCC as well as Director of Immunotherapy Clinical Trials.

"Collaborating with MSKCC and Dr. Wolchok's laboratory opens a new chapter in the development of our personalized cancer vaccine portfolio for targeting later stages of this disease," said Garo Armen, Ph.D., CEO of Agenus. "Partnerships with leading institutions are central to Agenus' strategy to bringing life-changing products for cancer patients to market faster."

Agenus' cancer vaccine is designed to expand and specifically program the army of T-cells responsible for killing tumor cells; however, as cancer grows it becomes smarter and increasingly builds an 'immune fortress' that can protect itself from the attack of T-cells. Therefore, combining a product that activates T-cells with an agent that blocks the signal preventing the T-cells from effectively killing the tumor could have highly potent outcomes.

"Combination immunotherapy in cancer is increasingly becoming a key focus of research, and this collaboration will add to this important and growing knowledge base," said Dr. Wolchok. "Our interest in Agenus' cancer vaccine is that it contains many antigens that are genetically matched with the cancer as the product is derived from the tumor itself."

"In addition to this preclinical research effort, we are looking forward to opportunities to rapidly initiate clinical trials, combining our Prophage series of cancer vaccines with either marketed or investigational agents that work against T-cell down regulation," said Dr. Armen.

Source:Personalized Cancer Vaccine in Combination With Novel Immunomodulatory Agents


Combinatorial therapy will lead us toward a cure. Mark my words.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Targeted therapy for metastatic melanoma: From bench to bedside..Jim Breitfeller

Targeted therapy for metastatic melanoma: From bench to bedside
Author: Wen-Jen Hwu, MD, PhD

Malignant melanoma is well known for its aggressive clinical behavior, propensity for lethal metastasis and therapeutic resistance. However, in the last decade, considerable excitement has been generated by the identification of genetic mutations in various components of signaling pathways involving melanoma initiation and progression, particularly those involved in the MAP and PI3 pathways. Most recently, clinical trials of pharmacological targeting of relevant molecular targets have demonstrated dramatic response even in patients with late-stage melanoma.

The emerging insights into the mechanisms of activation and negative regulation of innate and adaptive immunity to tumors have provided another breakthrough in melanoma therapy. A new family of immune-based agents of monoclonal antibodies that exert their functions by tampering with immune system cell molecules causing an enhancement of antitumor immune responses has entered clinical trials. In general, these new antitumor agents are designed to break down the barriers to tumor tolerance/immunity. This new group of agents holds promise for at least additive effects with conventional therapies, as well as signal transduction pathway targeted therapies.

Targeting signal transduction pathways

Several key genetic lesions governing melanoma initiation and progression have been identified, the earliest and most common being a point mutation (T1799A) in the BRAF proto-oncogene, which is detected in approximately 60% of metastatic melanoma. BRAFT1799A encodes BRAFV600E, a constitutively active protein serine kinase that elicits sustained activation of the BRAF® MEK1/2® ERK1/2 MAP kinase pathway.

In addition to BRAF, RAS oncogene (rat sarcoma viral oncogene homolog) is another constituent of the MAP kinase pathway. RAS mutations (in one of three isoforms) are found in approximately 20% of metastatic melanoma. RAS is capable of turning on several downstream pathways, including BRAF and other components of MAP kinase pathways, the PI3 kinase pathway, and the RAL-GDS pathway. In general, if a RAS mutation is present, there will be no BRAF mutation. However, the combination of mutated BRAF and silencing of PTEN expression is common in human melanoma (~20%). Dankort and colleagues have demonstrated in a preclinical model that “BRAFV600E cooperates with PTEN loss to induce metastatic melanoma.”

The prevalence of RAS/RAF alterations in human cancer has prompted significant efforts in the development of drugs targeting the MAP kinase pathway. Many of these are currently in clinical trials in patients with metastatic melanoma. Studies with the broad spectrum RAF inhibitor sorafenib (Nexavar, Bayer) as a single agent in patients with BRAF mutated melanoma have proved disappointing. What was unclear from these studies was whether the lack of efficacy was because BRAF was not a critical target or because of incomplete blocking of BRAF by sorafenib.

Since 2005, several BRAF inhibitors have entered clinical trials. These inhibitors are grouped in two categories: BRAF selective inhibitors, and broad spectrum multiple kinases inhibitors with high potency against BRAF.

BRAF inhibitors

PLX4032 (Plexxikon, also known as RO5185426) is a selective BRAF inhibitor and is the first of its kind tested in advanced melanoma. A response rate of 70% in 32 BRAF mutated melanoma patients was reported in the phase 2 study. In general, PLX4032 is well tolerated and most common toxicities include mild-to-moderate skin rash, sun sensitivity, fatigue, arthralgia and keratoacanthoma. Currently, there are two ongoing PLX4032 trials.


Wen-Jen Hwu

The first is a phase 2 study of PLX4032 as a single agent in BRAF mutated melanoma patients who have failed standard therapy for metastatic disease. This study will hopefully confirm the high response rates observed in previous phase 1/2 studies. The second is a phase 3 trial comparing PLX4032 with dacarbazine (standard chemotherapy) in chemotherapy-naive patients with BRAF mutated metastatic melanoma. Seven hundred patients will be enrolled; the primary endpoint is OS.

Another BRAF selective inhibitor is GSK2118436 (GlaxoSmithKline). This drug has already shown promising antitumor activity in the phase 1 portion of a study. The phase 2 portion is ongoing. The impressive high level of antitumor activity of BRAF selective inhibitors indicates that both PLX4032 and GSK2118436 have single-agent activity; BRAF is an important target in melanoma.

Currently, there are at least two nonselective BRAF inhibitors. XL281 (Bristol-Myers Squibb) and RAF265 (Novartis) are in phase 1 testing. Results are expected in the near future.

MEK is a kinase and is immediately downstream of BRAF. It is never mutated in cancer but is activated by BRAF and, in turn, activates the rest of the MAP kinase pathway. In the laboratory, MEK inhibitors have shown activity in a number of BRAF mutated cancers. Currently, there are many MEK inhibitors in clinical trials.

AZD6244 (AstraZeneca) is a MEK inhibitor that has been evaluated most extensively in melanoma. A phase 2 study comparing AZD6244 with temozolomide (oral chemotherapy) has found an objective response rate of 12% among 45 BRAF-mutated patients. However, patients in this study who received temozolomide had a similar response rate and PFS.

Melanomas from acral lentiginous, mucosal and chronic sun-damaged sites frequently harbor activating mutations and/or increased copy number in the KIT tyrosine kinase receptor gene, which are very rare in more common cutaneous melanomas. Multiple case reports and early observations from clinical trials suggested that targeting mutant KIT with small molecule KIT inhibitors such as imatinib (Gleevec, Novartis) and/or dasatinib (Sprycel, BristolMyersSquibb) is efficacious.

Although the dramatic clinical activity of BRAF selective inhibitors is a major breakthrough in the treatment of this disease, there are many hurdles to overcome to optimize this targeted therapy approach. Many of the patients who initially responded to PLX4032 have subsequently progressed with a median duration of response of approximately 8 months. The mechanisms that cause resistance are largely unknown.

Recently, a number of preclinical studies have demonstrated that BRAF inhibitors activate MEK and MAP kinases in melanoma cell lines with wild-type BRAF, including cell lines with mutant NRAS. These studies suggest at least one potential mechanism of resistance is through continued activation of the RAS-RAF-MEK-ERK signaling pathway. Thus, combination agents that target multiple components of this pathway have great potential to overcome drug resistance. Several ongoing clinical trials using the combination of BRAF and MEK targeted agents will be able to test this hypothesis.

Targeting tumor immunity barriers

Since the discovery of monoclonal antibodies in the late 1970s, it has become clear that these antibodies, which are of defined specificity and can be produced in large amounts, had potential for the management of various diseases, including malignancies.

The key property of antibodies to be used as therapeutic tools is their behavior as high-avidity ligands to protein or glycoprotein. Most recently, a new group of monoclonal antibodies that enhance the cellular immune response against cancer have entered clinical trials. These agents bind molecules on the surface of immune system cells. They either provide activating signals to lymphocytes and antigen presenting cells or block the action of receptors that normally down-regulate the immune response.

A humanized monoclonal antibodies (MDX-010, Medarex) against cytotoxic T-lymphocyte antigen 4 (CTLA-4) is the first to reach clinical trials. CTLA-4 is only expressed on the cell surface of activated T cells and regulatory CD4+ CD25+ T cells. In murine models, systemic treatment with transplantable immunogenic colon carcinoma cells with anti-CTLA-4 monoclonal antibodies induced complete tumor regression of established tumors through an immune response found to be critically dependent on the activity of cytotoxic T lymphocytes.

Various phase clinical studies have been conducted on the two anti-CTLA-4 monoclonal antibodies, ipilimumab (Bristol-Myers Squibb) and tremilimumab (Pfizer), as monotherpy, in combination with vaccines or other immunotherapies, and in combination with chemotherapies. Blockade by the T-cell inhibitory molecule CTLA-4 results in antitumor response with overall response rates from 10% to 20%. Most adverse events involve autoimmune toxicities, such as dermatitis, uveitis, colitis/enterocolitis, hepatitis and hypophysitis.

4-1BB (CD137) is a surface glycoprotein that belongs to the TNF receptor family. It is expressed by activated, but not resting, T and NK cells. A humanized anti-4-1BB monoclonal antibody (Bristol-Myers Squibb) has been tested in clinical trials. However, the phase 2 study in refractory melanoma was discontinued in May 2009 due to unusually high incidence of grade-4 hepatitis.

Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance and immunopathology. In vivo studies have shown B7-1 (CD80) is also a binding partner for PD-L1, and their interactions can lead to bidirectional inhibitory response in T cells.

PD-L1 is expressed on many tumors including melanoma and is a component of the immune suppression by the tumor microenvironment. Phase 1/2 experience of the anti-PD-1 monoclonal antibody, MDX-1106 (Medarex, Ono-4538), in refractory or relapsed malignancies was presented at the 2009 ASCO Annual Meeting. Clinical activity against melanoma was observed and, more importantly, no MDX-1106 related severe adverse events were noted.

In 2009, at M.D. Anderson Cancer Center, we participated in a phase 1 study of anti-PD-L1 monoclonal antibody (MDX-1105, Medarex) in refractory metastatic melanoma. MDX-1105 has been tolerated by all patients. Most adverse events were mild and were related to inflammatory responses in the tumors, not immune-related toxicity. Clinical responses were observed at all dose levels (1 mg/kg to 10 mg/kg every 2 weeks). Durable partial responses and stable disease were noted in patients whose disease had progressed after at least one, and as many as five, prior systemic therapies. Based on the low toxicity and impressive clinical activity, a phase 2 study of MDX-1105 in advanced melanoma is warranted.

In summary, the treatment of metastatic melanoma is changing rapidly due to the great success in translational research from bench to bedside. Although such studies, to date, have focused on the treatment of advanced metastatic disease, the approaches of targeting signal transduction pathway, as well as targeting tumor immunity barrier, hold great promise to the development of preventive strategies and personalized therapies in malignant melanoma.

Wen-Jen Hwu, MD, PhD, is a professor in the department of melanoma medical oncology at The University of Texas M.D. Anderson Cancer Center and is a member of the HemOnc Today Editorial Board.

Source:http://www.hemonctoday.com/article.aspx?rid=65856


“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

CryoStim™ Cancer Treatment to Begin FDA Clinical Trials September 1, 2009,,Melanoma,, Jim Breitfeller

CryoStim™ Cancer Treatment to Begin FDA Clinical Trials September 1, 2009

Date:8/14/2009[“CryoStim™ represents a completely novel approach for therapeutic cancer design,” says Michael Har-Noy PhD, CEO and Chief Technical Officer. “Current therapies are not capable of eliminating every last cancer cell in the body and thus tumor recurrence is a common problem. If our experimental therapy is successful it would be possible to not only eliminate every last tumor cells, but also for the immune system to remember the tumor in order to prevent recurrence.”

Details about this cancer vaccine trial can be found at www.immunocare.net and at clinicaltrials.gov: NCT00861107. View complete details on products, trial and scientific literature at the company website.

About Immunovative:
Immunovative Therapies, Ltd. (ITL) is an Israeli-based biopharmaceutical company with US facilities in Carlsbad, California. Founded in May 2004 with financial support from Israel’s Office of the Chief Scientist, ITL is a graduate of the Misgav Venture Accelerator, a member of the world renowned Israel technological incubator program. The company was the Misgav Venture Accelerator’s candidate for the prize for the outstanding incubator project of 2006, awarded by the Office of the Chief Scientist. ITL specializes in the development of novel immunotherapy drug products that incorporate bioengineered living immune cells as the active ingredients for treatment of cancer, autoimmune and infectious disease.

Contact:
Michael Berger MD at 760-444-9040

In the Pacific Northwest contact Alan F. Hall JD at 425-774-9566



Dr. Flavell,
After 2 ½ years of stabilization from my first response to Melanoma, it appears that I may have relapsed. I will know once I have a full PET scan. My question is, why didn't my memory cells kick in? Could you help shed some light on this subject matter?

Need a copy of your paper "CD8 and T Cell Memory"

RESPONSE:

Did you receive immunotherapy ( anti-CTLA4 or PD-1 )? There are Tregs which suppress the memory responses which you may have; were immune responses measured?.The data on these Antibodies are sounding good . Contact Mario Sznol(Yale) who is a melanoma physician; I am a Ph.D so of little help on the specifics. Which paper are you referring to; we will send it.
Good Luck with all RAF

It may all come down to "BLAME IT ON THE TREGS"

So is my body making to many Tregs during activation which is shutting down the immune response? How do we block them into a normal ammount?

We need to get our hands around the Tregs.



Take Care,

Jimmy B

Immunotheraphy of Melanoma - July 15, 2009 ..audio file Melanoma..Jim Breitfeller

http://www.melanoma.org/upload%5C2214.mp3


Immunotheraphy of Melanoma - July 15, 2009 ..audio file


the latest information on immunotherapies of melanoma. Whether you are newly diagnosed or are years after diagnosis, this program will provide quality information about melanoma. The conference is intended for patients with melanoma or friends or family member so that you have the information you need to understand melanoma from diagnosis, to treatment, to long term follow up.





Speaker: Jedd Wolchok, M.D., Ph.D.



Moderator: Lynn Schuchter, M.D.




After Dr. Wolchok’s presentation, there will be time for live question and answer period.





Take Care,

Jimmy B

The Role of the CTLA-4/PD-1 Pathway in Regulating T-Cell Response..Melanoma ..Jim Breitfeller

The Role of the CTLA-4/PD-1 Pathway in Regulating T-Cell Response

Jeffrey Weber, MD, PhD

The Role of the CTLA-4/PD-1 Pathway in Regulating T-Cell Response Flash Presentation

For those looking of information

Jimmy B

PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients.

This just came out!!!!!!!!!!

Dear James Breitfeller!

"Hot off the press - below is a roundup of recent papers
which have been authored by you, by one of your co-authors,
or from scientists in your contacts or bookmarks." Well I know I did not write this, so I must have been Dr. Kirkwood and Colleages


Fourcade Julien; Kudela Pavol; Sun Zhaojun; Shen Hongmei; Land Stephanie R; Lenzner Diana; Guillaume Philippe; Luescher Immanuel F; Sander Cindy; Ferrone Soldano; Kirkwood John M; Zarour Hassane M

Journal of immunology (Baltimore, Md. : 1950) 2009;182(9):5240-9

Department of Medicine and Division of Hematology/Oncology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.

"The programmed death 1 (PD-1) receptor is a negative regulator of activated T cells and is up-regulated on exhausted virus-specific CD8(+) T cells in chronically infected mice and humans. Programmed death ligand 1 (PD-L1) is expressed by multiple tumors, and its interaction with PD-1 resulted in tumor escape in experimental models. To investigate the role of PD-1 in impairing spontaneous tumor Ag-specific CD8(+) T cells in melanoma patients, we have examined the effect of PD-1 expression on ex vivo detectable CD8(+) T cells specific to the tumor Ag NY-ESO-1. In contrast to EBV, influenza, or Melan-A/MART-1-specific CD8(+) T cells, NY-ESO-1-specific CD8(+) T cells up-regulated PD-1 expression. PD-1 up-regulation on spontaneous NY-ESO-1-specific CD8(+) T cells occurs along with T cell activation and is not directly associated with an inability to produce cytokines.

Importantly, blockade of the PD-1/PD-L1 pathway in combination with prolonged Ag stimulation with PD-L1(+) APCs or melanoma cells augmented the number of cytokine-producing, proliferating, and total NY-ESO-1-specific CD8(+) T cells. Collectively, our findings support the role of PD-1 as a regulator of NY-ESO-1-specific CD8(+) T cell expansion in the context of chronic Ag stimulation. They further support the use of PD-1/PD-L1 pathway blockade in cancer patients to partially restore NY-ESO-1-specific CD8(+) T cell numbers and functions, increasing the likelihood of tumor regression. "


What does it mean?????

Programmed death-1 blockade (anti-PD-1 mAb) enhances expansion and functional capacity of human melanoma antigen-specific CTLs.

"The increased frequencies and absolute numbers of antigen-specific CTLs by PD-1 blockade resulted from augmented proliferation, not decreased apoptosis. Kinetic analysis of cytokine secretion demonstrated that PD-1 blockade increased both type-1 and type-2 cytokine accumulation in culture without any apparent skewing of the cytokine repertoire."

These findings have implications for developing new cancer immunotherapy strategies for Melanoma!!!!!!!

I believe Yale and MD Anderson have trials with the Moffit Center in Flordia coming on soon.

Jimmy B

Inducing a Immune Response.. Melanoma ..Jim Breitfller

The best way to fight cancer (Melanoma) in my opinion is to have your own immune system do the work. First one must activate the T-cells.
Activation of T cells requires both engagement of the (TCR) T Cell Receptor with a cognate peptide–MHC complex and an additional costimulatory signal. The antigen must be in the right configuration and be specific to the cancer. The antigen becomes part of the MHC complex. The T cell receptor is restricted to recognizing antigenic peptides only when bound to appropriate molecules of the major histocompatibility complex (MHC), also known in humans as Human leukocyte antigen (HLA).
Secondly one must have a co-simulative signal.

The best known co-stimulatory ligands (proteins) are members of the B7-family, B7-1 (CD80) or B7-2 (CD86), that are expressed on professional antigen-presenting cells (APCs) such as dendritic cells (DCs); these act through their receptor CD28 on T cells CTLA-4 (CD152) is a second receptor for CD80 and CD86, which is not expressed on most resting T cells but is induced upon T-cell activation. The interaction of CD80/CD86 with CTLA-4 has higher affinity than that with CD28, and down-regulates T-cell activation . Thus, CTLA-4 effectively competes with CD28 for CD80/ CD86 at later stages of the immune response to suppress the activation and bring about activation-induced nonresponsiveness (AINR) and/or activation-induced cell death (AICD). Down-regulation of T-cell function by CTLA-4 engagement appears to play a key role in development of T-cell tolerance or anergy towards self- or tumor antigens while antigenic stimulation in the absence of co-stimulatory signals is also tolerogenic.

So by introducing anti-CTLA-4, one can block the down-regulation of the T-cell and keep it activated for a longer period of time. By anti-CTLA-4 blockage, one can suppress the Treg and change the balance of the immune system to respond to the APC. Here is a list of Costimulatory receptors on T –Cells:

• CTLA-4
• PD-1
• 4-1BB
• HVEM
• CD 30
• OX40
• CD28
• CD27

By Treg depletion, you can also break the balance of anergy. Dr. Rosenberg uses Treg depletion prior to Adoptive Cell Transfer therapy.

Bottom line is you need to invoke this type activation to orchestrate an immune response.

Take care

Jimmy B

Melanoma Update: Highlights of research presented at ASCO and an update on vaccines trials.Melanoma..Jim Breitfeller

Issue Number:
Volume 17 - Issue 3 - March 2009
author:
John Otrompke, Contributing Editor
Mixed Melanoma Trial Results Point to Need for Tailored Studies

"Effective melanoma therapies may be inching forward, with a number of the new class of potential therapeutics in the pipeline entering Phase III trials, and researchers presenting some of the first published data on other agents at this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

But with mixed results, some disappointing, some surprising, some researchers say clinicians and clinical trial designers must rethink development strategies, including patient selection, if some of the new class of biological therapeutics for melanoma are to make significant headway.

“The problem with melanoma is that, other than surgery, there really are no very good effective therapies. The chemotherapies that are out there are not curative but palliative treatments,” explains David Solit, MD, Elizabeth and Felix Rohatyn Chair and Assistant Attending Physician, Department of Medicine, Sloan-Kettering Cancer Center.

But medical science is progressing, says Dr. Solit, who spoke at the ASCO conference. “We actually know a lot of the genetic alterations that cause the cancer. In 2002 there was a mutation in a protein called BRAF that was identified, and the mutation is found in the tumor in 50% to 70% of patients with melanoma. Then there’s a protein called NRAS, which also gets mutated in 15% to 20% of melanoma patients. But when you have an NRAS mutation, you don’t have a BRAF mutation. In total, between 60% and 90% of patients have one of the two,” says Dr. Solit, who gave the presentation, “Genetic Predictors of RAF/MEK Dependence.”

But the news at ASCO was not all good for the new therapies.

Early Promise, Mixed Results

Some of the most important new strategies for treating advanced melanoma focus on the patient’s immune system.

“Two of the strategies use anti-CTLA 4 and anti-PD1 agents to take the brakes off the patient’s immune system. Both are receptors on a patient’s T-cells, which are part of the normal braking system, which is a good thing at most times, but not a good thing in regards to a cancer cell,” says Walter Urba, MD, PhD, Director of Cancer Research at the Earle A. Chiles Research Institute in Portland, Oregon.

“The other two strategies use antibodies 41BB or OX 40. At ASCO this year, we saw some late clinical trial results with the anti-CTLA 4 product, and the first published results with anti-41BB and anti-PD1,” says Dr. Urba, who also discussed very early results with his own institution’s investigational agent, OX 40.

A disappointing trial of a new potential therapeutic agent was a head-to-head trial of an agent called a MEK inhibitor, which was tested against temozolomide, a standard pre-existing chemotherapy for melanoma. There was no significant difference between the standard arm and the MEK inhibitor (AZD 6244 by Astra Zenaca), according to the trial results.

However, patient selection may be the problem. “Genetic differences are relevant, because the BRAF mutation found so often in melanoma patients, activates a protein called MEK. “If you have a RAF mutation, you may respond a lot better to a MEK inhibitor,” explains Dr. Solit, noting that in addition to the Astra Zenaca drug, another MEK inhibitor in research is a drug from Pfizer called PD 0325901. The Astra Zenaca drug, which encountered the disappointing result, is in Phase II trials, whereas the MEK inhibitor from Pfizer is only in Phase I.

“The problem with the Astra Zenaca trial is that they didn’t look for BRAF-mutated patients. It’s possible temozolomide is as good or better than AZD 6244 in unselected patients, but five of the six responders in the MEK inhibitor arm had BRAF mutations,” Dr. Solit says. “There is technology out there already to start looking for these mutations, and it has already become routine in lung cancer for other genes.”

There were some positive, surprising results presented as well, however. A Phase II trial of ipilimumab, an investigational immunomodulatory agent from Bristol Meyers Squibb, which is in late Phase III trials, was studied in a population of 115 patients in combination therapy with Budesonide, a currently existing therapy. “Our primary endpoint was to see whether in a randomized trial we could reduce the amount of diarrhea that occurs as a side effect of the Budesonide, and our primary endpoint was not successful, but ironically, the clinical results were outstanding. Our median survivals were over a year,” says Jeffrey Weber, MD, PhD, Director of the Donald A Adam Comprehensive Melanoma Research Center and Professor of Oncologic Sciences at the University of South Florida.

Updated survival data of three Phase 2 studies of ipilimumab in patients with metastatic melanoma (Stage III or IV) who had previously been treated were presented at the European Society for Medical Oncology in Stockholm. Study results show that approximately half of patients who received ipilimumab (10 mg/kg) remained alive beyond 1 year. The results are based on follow-up of the patient population from studies 008, 022 and 007 treated with 10 mg/kg of ipilimumab (induction and maintenance) and show a consistent 1-year survival rate between 47% and 51%.

Combination Therapies of the Future, Today

Another promising strategy offering hope to advanced melanoma patients is to stimulate the patient’s immune system, by mimicking signal’s sent naturally by the body.

“We have learned from studying patients with melanoma just how powerful the immune system can be, but we need to supplement the response, and free it from some of its limitations,” says Robert H. Vonderheide, MD, Assistant Professor of Medicine at Abramson Cancer Center at the University of Pennsylvania.

The immune response in melanoma patients can be so pronounced that in rare cases, tumors even shrink in the face of it, says Dr. Vonderheide.

Dr. Urba agreed. “The immune response in melanoma is different from other cancers,” he explains. “One of the thoughts is that melanoma tumors are more immunogenic. Sometimes the response occurs after disease progression. In a couple percent of every patient population, the patient comes in and looks for all the world like they’re having tumor progression, and they end up having the tumor go away in response. The rationale is, that maybe it takes time for an immune response to build up and eliminate tumor cells following these investigational therapies,” he says, noting that these delayed responses can occur 8 or 12 weeks following therapy.

To attempt to take advantage of melanoma’s unique immunogenicity, Pfizer has developed an investigational agent that acts on an immune receptor called CD40, according to Dr. Vonderheide. “This is an antibody that binds to CD40 and mimics the signal sent to activate the immune system.”

The CD40 agonist has been tested by itself and in conjunction with standard chemotherapy drugs carboplatin and paclitaxel. The first clinical trial with the agent started about 4 years ago, and was reported 2 years ago at ASCO. Though the drug is only in Phase I trials, “taking it to Phase II is definitely warranted,” notes Dr. Vonderheide. “In the second study, we saw clinical activity: one patient has regressed, and remained in remission for years.”

In another study, the CD40 agonist will be given, along with chemotherapy, every 3 weeks, and the trial is enrolling as many as 30 patients, according to Dr. Vonderheide.

With some of the therapies, lack of experience in testing them may lead to unpredictable future results; in others, the sheer longevity of their period in trials can lead to skepticism.

“Anti-CTLA 4, an anti-inhibitory drug, has probably been in clinical trials for about 7 years, whereas anti-PD1, which is also an anti-inhibitory drug, has probably not been in trials for much more than a year,” says Dr. Urba, noting that the 41BB has also been in trials for 2 years.

For some drugs, clinical trials have enrolled hundreds of patients over the years, while other novel agents have only been tested in a few dozen humans. “The delayed response phenomenon, for example, has not been seen with other agents besides ipilimumab and tremilimumab, but with the other agents, the number of patients who have been treated is so small I’m not sure if we would have seen it,” he adds.

Still, the novel agents, whether young or old, often offer the only hope for advanced melanoma patients to hold onto.

“Nonetheless, it’s probably going to be a long series of trials to figure out which are the patients who are going to benefit. It’s a targeted therapy, and it doesn’t work for everybody. But we have insight into who it would work in, and we need to incorporate that information into our clinical trial design,” Dr. Solit says."


source: http://www.skinandaging.com/content/melanoma-update-highlights-research-presented-asco-and-update-vaccines-trials

Melanoma Update: Highlights of research presented at ASCO and an update on vaccines trials


Take care
Jimmy B

The B7 Family and Cancer Therapy: Costimulation and Coinhibition..Melanoma..Jim Breitfeller

www.aacrjournals.org Clin Cancer Res 2007;5271 13(18) September 15, 2007

Authors: Xingxing Zang and James P. Allison

Abstract: "The activation and development of an adaptive immune response is initiated by the engagement of aT-cell antigen receptor by an antigenic peptide-MHCcom plex.The outcome of this engagement is determined by both positive and negative signals, costimulation and coinhibition, generated mainly by the interaction between the B7 family and their receptor CD28 family. The importance of costimulation and coinhibition of T cells in controlling immune responses is exploited by tumors as immune evasion pathways. Absence of the expression of costimulatory B7 molecules renders tumors invisible to the immune system, whereas enhanced expression of inhibitory B7 molecules protects them from effectiveTcell destruction. Therefore, the manipulation of these pathways is crucial for developing effective tumor immunotherapy.Translation of our basic knowledge of costimulation and coinhibitioninto early clinical trials has shown considerable promise."

Source:http://clincancerres.aacrjournals.org/cgi/reprint/13/18/5271.pdf

The B7 Family and Cancer Therapy: Costimulation and Coinhibition



If you do anything, Please read this paper!!!

Jimmy B

Novel Treatment Approaches For Patients With Metastatic Melanoma (Page 4 of 5)

New Immunomodulatory Agents in Development

Four types of new immunomodulatory agents are in development for use in patients with malignant melanoma, including STA-4783, a heat shock protein inducer; PD-1 antagonistic antibody; anti-41-BB (CD137) antagonistic antibody; and CD40 agonistic antibody.

Heat shock protein inducer.

STA-4783 is a novel agent that promotes natural killer cell activity and augments levels of heat shock protein 70.[28] It is active as a single agent and with a taxane in human xenografts in mice. In phase 1 studies, STA-4783 appeared to have little clinical activity in kidney cancer or melanoma. In a randomized phase 2 study[29] that included 84 patients, STA-4783 plus paclitaxel were administered weekly intravenously for 3 weeks on/1 week off until progression or dose-limiting toxicity. The primary study end point was PFS. An intent-to-treat analysis found that PFS was 112 days for the combination of STA-4783 plus paclitaxel vs 56 days for paclitaxel alone (P = .035). The RR was 15.1% in the combination group vs 3.6% for the paclitaxel group. Patients in the combination group had a 54% grade 3/4 adverse event rate, compared with 57% for the paclitaxel-alone group. STA-4783 is being studied further in a phase 3 randomized registration trial.

PD-1 antagonistic antibody.

PD-1, a member of the TNF super-family, is another inhibitory molecule present on T cells.[30] PD-1 is increased on activated T cells and can bind to the PDL-1 molecule present on macrophages and dendritic cells as well as many tumors. The PD-1/PDL-1 interaction appears to limit the immune response, acts as a down-modulatory influence on antigen-specific immunity, and may represent a means by which tumors actively suppress immunity.A human immunoglobulin G4 antibody has been prepared that binds to and abrogates the activity of PD-1. In vitro, it can significantly augment the proliferation and functional activity of activated T cells; it is active alone, with chemotherapy, or with CTLA-4 abrogating antibodies in different murine tumor models.[31] This antibody has been tested in a phase 1 trial and thus far has not resulted in any dose-limiting toxicities after single dosing.

CD40 agonistic antibody.

CD40 is a receptor expressed on a variety of immune cells, including B cells and antigen-presenting dendritic cells.[32] It is bound by CD40 ligand expressed on T cells and represents an important axis of stimulation for antigen-specific T cells. An agonistic CD40 antibody, CP-870893, has been tested in a phase 1 single-dosing study, predominantly in patients with melanoma, at doses ranging from 0.03 to 0.3 mg/kg.[33] The reported side effects consist of chills and fevers, with deep venous thrombus and headache being the dose-limiting toxicities. Among 29 patients in the trial, 4 of 15 (27%) with melanoma sustained a PR at day 43 after only 1 dose of CP-870893. All responders received the drug at a dose level of 0.2 mg/kg or above, suggesting a dose-response relationship. Multidose phase 2 trials are pending for this promising agent.