How to integrate immunotherapies into treatment timelines? Timing is everything! Melanoma..Jim Breitfeller

Dr. Gomella,

I want to thank you for sharing your thoughts on immunotherapy in the article in “High Points and Hurdles: Immunotherapy Moves Forward” online at OncLive.

As a patient/survivor/researcher of stage IV melanoma I know first hand of the importance of integrating immunotherapy into a patient’s treatment. Timing of the therapy is everything, along with the patient’s tumor burden and stage.

In the early phase of cancer, the tumor cells are trying to establish a foothold in a foreign land. They do this by recruiting Tregs with cytokines (Il-10, TFG-b etc.) along with chemoattractants and suppressive cells.

Two of the first arrivals are Tregs along with IL-10. In the early phase of cancer, it has been discovered that the patient’s Tregs are elevated along with IL-10 concentration.

So when the macrophages and immune cells arrive at the tumor’s microenvironment, they encounter suppressive conditions allowing the tumor to continue with growth and progress. The elevated IL-10, IL-4 concentration polarizes the monocyte to the M2, and the T-cells to the Th2 phenotypes and shutting down the immune response.

The macrophage also secretes some chemokines (CCL17, CCL22& CCL18). These chemokines attract other cells that have the cell surface chemokine receptors such as CCR4.


Treg cell migration to Melanoma tumors is mediated by CCL22 released by cancer cells and tumor-associated macrophages. This cytokine plays a role in the trafficking of activated/effector T-lymphocytes to inflammatory sites and other aspects of activated T-lymphocyte physiology. Chemotactic for monocytes, dendritic cells and natural killer cells. Mild chemoattractant for primary activated T-lymphocytes and a potent chemoattractant for chronically activated T-lymphocytes but has no chemoattractant activity for neutrophils, eosinophils, and resting T-lymphocytes This attraction is the beginning of the suprresiveness of the the tumor’s microenviroment.

TAM exert strong immune suppressive activity, not only by producing IL-10 but also by the secretion of chemokines (e.g., CCL17 and CCL22), which preferentially attract T cell subsets devoid of cytotoxic functions such as Treg and Th2.


IL-10 promotes the development of a type 2 cytokine pattern by inhibiting the IFN-γ production of T lymphocytes particularly via the suppression of IL-12 synthesis in accessory cells.

IL-10 suppresses many functions of (NK) cells and T cells, primarily by preventing APCs from producing proinflammatory cytokines

So how can we integrate immunotherapies into treatment timelines to generate the wanted immune response toward the cancer?

1. First, you need to evaluate the cancer patient and establish their stage.
2. Second, check the tumor’s genetic code for mutations.


3. Third, evaluate the patient’s overall health and the ability to go through the therapy
   
   Here is a generic graphic on how to activate an innate and adaptive response.

1) You need to generate tumor-associated Antigens


2) You need to generate “The Danger Signal” (proinflammatory cytokines secreted, IL-1, IL-6, IL-12, TNF-alpha, Nitric Oxide, PGE2)

3) Block the Suppressive factors that inhibit T-cell activation (Anti-CTLA-4, Anti-PD-1, Anti IL-10r) IL-10 suppresses many functions of (NK) cells and T cells, primarily by preventing APCs from producing proinflammatory cytokines, “The Danger Signal”)

4) Tilt the T-cell Differentiation toward the TH1 phenotype and the Macrophage (TAM), Tumor Associated Macrophage polarization toward the M1 phenotype

5) Alter the tumor’s Microenvironment (addition of Multikine)

6) Produce activated CTLs and Memory T-cells(addition of IL-2)

The Bottom line is we need Sequential Combinatorial Therapy with timing and dosage as the major limiting factors in creating the innate and adaptive 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

Trying to take the guess work out of finding the correct immunotherapy for Melanoma Patients.Jim Breitfeller

As a stage IV survivor/researcher of Melanoma, I know first hand how it feels to be diagnosed with stage IV cancer. You, your family and your caretaker becomes overwhelmed by the information that must be absorbed and processed to make an educated decision on what therapy you want to try. Don’t get me wrong, your oncologist will play a major in your decision, but is it the right one? Is he trying to fill some of his clinical trials or is he looking out for your best interest? Armed with the right information, one can make the best possible choice. It shouldn’t be a hit or miss approach because with cancer, time is of the essence. Getting to the right therapy before you end up at the late stage IV of your disease is the name of the game. In my therapy, that was my goal, find the right therapy before it overcomes your internal organs and kills you. So, in 2005, I asked my doctor John M Kirkwood if they would take my tumors and biopsy them for gene analysis. Back in 2005, this analytical activity was revolutionary and not done as a standard of care. So in 2005, I contacted Arlet Alarcon from the Molecular Profiling Institute. I tried to convince Dr. John M. Kirkwood, but it was not to be. But now to fast-forward to 2012 and you will see molecular profiling your tumor becoming common practice. So with this in mind, here are some suggestions to get you on the right path. 1.) Assemble a team of doctors that specialize in your cancer. 2.) Make sure they see you as a major part of the team and the decision making. (Be your own advocate) 3.) Learn the medical language so you can research and stay abreast of the new therapies that are being discovered daily. 4.) Learn how your immune system works and how the therapies interact with the immune system. 5.) Be POSITIVE!!!
Here is the latest slide from "Evolving Treatment Options in Melanoma: Utilizing Genetic Features to Optimize Therapy" by Dr. Ribas

permission granted from Clinical Care Options – Oncology http://www.clinicaloptions.com/oncology.aspx SOC= Standard of Care

What I am trying tell is that by optimizing your personal therapy, you can extend your survival. “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

ACTION! Help Save the Life of Darcy Doherty, Father of Three Children to get immunotherapy drug for melanoma..Jim Breitfeller

ACTION! Help Save the Life of Darcy Doherty, Father of Three Children to get immunotherapy drug Anti-PD-1 (BMS-936558)  for melanoma.




Please write to Dr. Elliot Sigal at Bristol Myer Squibb
Elliott.Sigal@bms.com

Dr. Sigal is the Director of Research at BMS.
Please send a note to Dr. Sigal requesting that BMS open compassionate use for Mr. Doherty. I know it is a long shot/ Hail Mary Pass but, base on my research, this drug with the combination of IL-2 may be able to beat the odds.

Bristol Myer Squibb says "At Bristol-Myers Squibb, we are firmly focused on our Mission to discover, develop and deliver innovative medicines that help patients prevail over serious diseases."

Is this all lip service? Let see if BMS puts their money where their mouth is and grant this compassionate care use for this derserving family. Doherty with his clinal trial of Yervoy (Anti-CTLA-4 therapy) helped get the drug FDA approved through his survival data. The least Bristol could do is to grant the dying man compassionate use of the next generation drug called Anti-PD-1, (BMS-936558)

Bristol-Myer Squibb needs to show some compassion.

It is their ETHICAL Responsibility.


“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

 

A very Happy Father's Day from a stage IV Melanoma Survivor..Jim Breitfeller

I want to thank all the people that has made this day a very special Day.


As a stage IV Melanoma Survivor, I never dreamed that I would be here today to witness my children spread their wings and learn to fly. My daughter was just entering college when I was first diagnosed and my son, Chris was a sophmore in High School. Today, I am preparing to help my son relocate to Connecticut. He just landed an engineering job at an areospace company. My daughter, Jessica is globe-trotting around the world working on her dual Masters in "International Affairs" and "Natural Resources & Sustainable Development". This day, marks Dee and I as offically "Empty Nesters".

This all was made possible by entering a journey that entailed four clinical trials along with the best and internationally renowned medical team that makes climbing Mt. Everst apiece a cake. And you , My carepage friends that kept me on the "Yellow Brick Road". I have won the "lottery of life."

Many Thanks

“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
 

Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid Melanoma tumors: Clinical activity, safety, and a potential biomarker for response.Melanoma ..Jim Breitfeller

I have been following this new treatment for a number of years and am trying to get my arms around the science.

When a T-cell is activated, the PD-1 , CTLA-4, ICOS, and others molecule are expressed and upregulated to the surface of the T-cell. Both PD-1 and CTLA-4 are checkpoint molecules that regulate the immune response. They are inhibitory to the point that they can shut down T-cell activation. ICOS on the other hand is a costimulatory molecule that is needed, along with IL-2 to keep the T-cell activated and help proliferate the T-cells.Elevated levels of ICOS mRNA can be detected already one hour after TCR engagement, followed by surface expression within 12 hours. Protein expression reaches a maximum after 48 hours and declines then slightly.

It has been shown that ICOS is inducible within 48 hours of T  cell activation on both CD4+ and CD8+ cells  after  CD28 signaling  whereas cytotoxic T lymphocyte  antigen-4 (CTLA-4) ligation prevents its upregulation.

First, CTLA-4 engagement on resting T-cells was found to indirectly block ICOS costimulation by interferring with the signals needed to induce ICOS cell surface expression. Second, on preactivated cells that had high levels of ICOS expression, CTLA-4 ligation blocked the ICOS-mediated induction of IL-4, IL-10, and IL-13, suggesting an interference with downstream signaling pathways. The addition of IL-2 not only overcame both mechanisms, but also greatly augmented the level of cellular activation suggesting synergy between ICOS and IL-2 signaling.

So after T-cell Activation, IFN gamma is secreted (30 minutes), then IL-2 is secreted (45 minutes in) and so on,

The surface expression of ICOS is within 12 hours of activation. Since CTLA-4 blocks ICOS costimulation, Yervoy (anti-CTLA-4) must be used to counter the surpressive signalling. PD-1 also upregulates to the surface in the early activation process. PD-1 is upregulated within 24h after T cell activation.PD-1-Mediated Suppression of IL-2 Production Induces CD8+ T Cell ... anergy was associated with a marked down-regulation of IL-2.

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.

PD-1 blockade seem to augment the proliferation of the CD4+ helper cells.

Now you know why just using Anti-PD1 and or Yervoy as a monotherapy will not have a large response rate. Combinational Therapy is a must if we are to see synergistic responses. IL-2 also plays a major roll in the immune response. IL-2 is added to help maintain fuctionality and survival of the Cytotoxic T Lymphocytes (CTLs) that is despartly needed to eradicate the Melanoma tumors. Our immune system can cure cancer, I am living proof of it.

Jimmy B



“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

Immunotherapy of cancer in 2012..Melanoma ..Jim Breitfeller

This is a great summary of Immunotherapy as we know it today. A must read for cancer patients, caregivers, Oncologists.

Download it today!!!
Melanoma Immunotherapy of cancer in 2012

It is somewhat technical but should be in the patient's, caregiver's and Oncologist's library. Knowledge is power. Power to heal ones disease.


“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

 

Macrophage Activation… The Missing Link to Activation an immune response to Melanoma..Jim Breitfeller

"The development of Th1 cells producing high levels of IFN-gamma could not be induced with dendritic cells alone but required the addition of appropriately activated macrophages." Et al A. O'Gara March 23, 1993 "Dendritic cells and macrophages are required for Th1 development of CD4+ T cells from αβ TCR transgenic mice: IL-12 substitution f.or macrophages to stimulate IFN-γ production is IFN-γ-dependent"
Local IL-12 therapy stimulates Th cells to secrete Th1 cytokines. Exogenous IL-12 application creates an environment rich in IL-12 around the cancer site. In such a local environment, newly activated Th cells, responding to the presence of cancer, exit the blood and are influenced to become Th1 cells and secrete more Th1 cytokines and activate macrophages and NK cells. Activated macrophages will produce more IL-12 and via positive feedback, cell-mediated immunity can be promoted to battle the cancer thereby leading to the prevention of reoccurrence. As you can see, the activated macrophage secretes IL-12, IL-1a, IL-1b, and IL-6 along with a Chemoattractant, IP-10. Without macrophage activation, the immune response does not take place and the patient will relapse.(see graphic below)

With IL-1b and IL-6 missing, the T-Regulatory Cells (Tregs) rule the Tumor's Microenviroment. IL-6 controls Th17 immunity by inhibiting the conversion of naive CD4+ T cells into Foxp3+ regulatory T cells. IL-1β–Mediated Signals Preferentially Drive Conversion of Regulatory T Cells but Not Conventional T Cells into IL-17–Producing Cells (Danger Signal).So if the IL-1b signaling is missing,conversion of the Tregs never take place along with no Danger Signals.

Dr. Steven Rosenberg is using engineered T-cells that secrete IL-12 to stimulate Th cells to secrete Th1 cytokines. This sets in motion the positive feed back loop needed to initiate an immune response. His therapy is show great promise. “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

ASCO Review with Dr. John Kirkwood on Melanoma Therapies..jim Breitfeller

The full Audio of the Dr. Kirkwood interview at ASCO 2011


Please if you get a chance, listen to the full interview of Dr. John Kirkwood on the lastest therapies for Melanoma. It might help save your life or loveone's life.

Get a cup of coffee and a pad and pencil.

Enjoy




“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

Activating the Danger Signal with Anti-CTLA-4 Blockade..Melanoma..Jim Breitfeller

Melanoma Stats
Initial Diagnosis: May 2003
Current Stage: Stage 4
Depth of Primary: Up to 1 mm
Treatment Stats
Doctor: Mario Sznol MD
Treatment Center: Yale New Haven
Clinical Trial(s): Ipilimumab
Treatment History
February, 2003 my wife noticed a dark spot on my balding head.

April 2003 Punch biopsy read asmelanoma, 0.76mm deep.

May 2003 Wide Local Excision

May-Sept - Multiple dysplastic nevi excised

Sept 2003 - Second primary, this time in situ, on my chest

PET scan, MRI and CT all negative

Oct 2003 - University of Pennsylvania Pigmented Lesion clinic in Philadelphia they reread my slides and reclassified it to a Breslow's depth of 0.86 and Clark's level 4 and told me I have Stage 1B with a specific note that there appeared to be no immunologic response by my body to the melanoma.

October 2003 - October 2006 Derm exam every 3 months. Many dysplastic nevi excised. Doing well, no more primaries, no problems.

October 2006 coughed up blood CT, PET showed a 5cm mass in my L lung. MRI negative for brain mets. No other lesions found.

October 30, 2006 - Thoracotomy at St. Peter's Hospital in Albany NY with removal of the lower lobe of my left lung. Did well after surgery.

November, 2006 - Local oncologist offers interferon but suggests I look into trials

December, 2006 - Accepted into University of Pennsylvania trial of Anti-CTLA4 if my scans remain clear

December 12, 2006 - Had MRI and CT for study and found I has a previously undiagnosed.
met to my brain
December 13, 2006 - Radiation oncologist suggests neurosurgery unless it is not safe to resect. Also heard I may have micro-mets in the lungs. Put on decadron. Seeing neurosurgeon on 12/14

December 14, 2006 - Neurosurgeon says "take it out"

December 20, 2006 - Craniotomy. Second major surgery in 7 weeks! Another stint in the ICU. Woke up unable to move my left leg

December 24, 2006 - One week in a rehabilitation hospital. Intense physical therapy and I walk out

January 2007 - Planned on SRS but more brain mets found. Underwent 15 sessions of WBR

March 2007 - More lung mets found - multiple, disseminated in both lungs, tiny

April 2, 2007 I start IL-2 at Deaconess Beth Isreal in Boston

June, 2007 Brain tumors bleed - emergency craniotomy

July, 2007 - Stereotactic radiation

Sept, Oct waititg for a trial...and waiting...and waiting



October 2007 Accepted in compassionate use trial WITH Ipilimumab (MDX-010 at Yale New Haven Hospital under the care of Dr. Sznol

October 31, 2007 First dose of Ipilimumab at Yale-New Haven Hospital.

November 20, 2007 Second Infusion of Ipilimumab

December 11, 2007 Third dose of Ipilimumab

December 18, 3007 Severe reaction to IPI
Admitted to YNHH with uncontrolled vomiting, dehydration, hyponatremia and weakness. Discharged December 23, 2007 to home. Began 4 mg oral steroids.

January 22, 2008 began to notice double vision, nausea and vomiting as steroids were tapered from 3mg to 2 mg. Steroids increased to 2.5 mg

January 23. , increased to 3mg
anuary 25, increased to 4 mg

January 28, 8 mg January 29 . Nausea and vomiting disappeared. Double vision improvement noted

February 4th…Have lost all peripheral vision.

March 2008 increased weakness noted in lower extremity resulting in confinement to
Wheelchair and walker. MRI noted area of increased swelling on right parietal lobe at site of June 2007 surgery. Not metastatic disease.

April 2008 prescribed high dose (40mg) oral steroids to reduce swelling and manage side effects until planned surgery May 2008.

May 8 2008 planned craniotomy (#3) to remove necrotic tissue iAfter 5 day inpatient stay, walked out of hospital without assistive device. Began taper of steroids.

May-June 2008 unable to tolerate steep taper, steroids increased and taper resequenced at much slower rate.

December 2009 Tumors still visible on scans in brain and lungs but no growth since 2008, Stable. No evidence of active disease.

UPDATE written October 7 2010

October 7, 2010. Four years after my diagnosis with Stage IV Melanoma I continue to show no evidence of active disease. I do have problems elated to treatmens: Simple Partial Seizures, Visual problems (Double and blurred) Short term memory loss, Episodes of fatigue. Symptoms that remind me about what I went through these past four years, but definitely things I CAN LIVE WITH. A hell of a lot better than I thought when I started to fighting the beast/
Mark, Catskill, NY




Activating the Danger Signal with Anti-CTLA-4 Blockade





Was it the combination Radiation, IL-2 plus the Anti-CTLA-4 blockage?




“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

CTLA-4 Ligation Blocks CD28-dependent T Cell Activation..Melanoma.Jim Breitfeller

CTLA-4 Ligation Blocks CD28-dependent T Cell Activation


Summary:
CTLA-4 is a CD28 homologue beheved to be a negative regulator of T cell function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the effect of CTLA-4 ligation on cytokine production, cell survival, and cell cycle progression. The results demonstrate that the primary effect of CTLA-4 ligation is not the induction ofapoptosis. Instead, CTLA-4 signaling blocks IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells. Moreover, the effect of CTLA-4 signaling was manifested after initial T cell activation. Inhibition oflL-2 receptor expression and cell cycle progression was more pronounced at late (72 h) time points after initial activation. The effects of anti-CTLA-4 mAbs were most apparent in the presence of optimal CD28-mediated costimulation consistent with the finding that CTLA-4 upregulation was CD28-dependent. Finally, the addition of exogenous IL-2 to the cultures restored IL-2 receptor expression and T cell prohferation. These results suggest that CTLA-4 signaling does not regulate cell survival or responsiveness to IL-2, but does inhibit CD28-dependent IL-2 production.


CTLA-4 Ligation Blocks CD28-dependent T Cell Activation


“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

Unleashing the Immune System to Destroy Melanoma..Jim Breitfeller

Applying dosing schedules to the clinical protocols of combinatorial therapy, we can optimize the clinical outcome 4-14-2010




The Making of an Immune Response using Anti-CTLA-4 Blockade with Interluekin 2

There is one missing link in all of this. The "DANGER SIGNAL"

How do we generate the Danger Signal so our immune system knows that there are foreign invaders (Melanoma Cancer cells)are present? I have been researching this for quite some time now. I call it the "Missing Link". Bristol Myer Squibb thinks that their Ipilimumab can be used as a monotherapy, but they are mistaken. They want you to believe that their drug is doing all the work but behind the sences there is real Biochemistry taking place. Interluekin-2 is one of the most important players in this Orchestra.

In the next couple of weeks I will elaborate on my theory of the Danger Signal and reveal the pieces of the puzzle that i have discovered in my research.

But for now, let the light shine on Ipilimumab, (anti-CTLA-4 blockade) from Bristol Myer Squibb


“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 quantal theory of how the immune system discriminates between "self and non-self"..Melanoma..Jim Breitfeller

The quantal theory of how the immune system discriminates between "self and non-self"
Kendall A Smith
2004

If you get a chance to read this paper; You will now know why, the combinatorial therapy of Anti-CTLA-4 Blockade and HD Interluekin-2 will work on jump starting your Immune System.

Please take your time in reading this paper. It could save your Life!!!

"In the past 50 years, immunologists have accumulated an amazing amount of information as to how the immune system functions. However, one of the most fundamental aspects of immunity, how the immune system discriminates between self vs. non-self, still remains an enigma. Any attempt to explain this most intriguing and fundamental characteristic must account for this decision at the level of the whole immune system, but as well, at the level of the individual cells making up the immune system. Moreover, it must provide for a molecular explanation as to how and why the cells behave as they do. The "Quantal Theory", proposed herein, is based upon the "Clonal Selection Theory", first proposed by Sir McFarland Burnet in 1955, in which he explained the remarkable specificity as well as diversity of recognition of everything foreign in the environment. The "Quantal Theory" is built upon Burnet's premise that after antigen selection of cell clones, a proliferative expansion of the selected cells ensues. Furthermore, it is derived from experiments which indicate that the proliferation of antigen-selected cell clones is determined by a quantal, "all-or-none", decision promulgated by a critical number of cellular receptors triggered by the T Cell Growth Factor (TCGF), interleukin 2 (IL2)."
The quantal theory of how the immune system discriminates between "self and non-self"





“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

High Dose Interluekin-2 followed by low-dose metronomic temozolomide (TMZ) to induce a complete immune Response.Melanoma ..Jim Breitfeller

High Dose Interluekin-2 followed by low-dose metronomic temozolomide (TMZ) to induce a complete immune Response

Background
CD4+CD25+ regulatory T cells (Treg), which constitute about 2–3% of CD4+ human T cells, are the main contributors to the maintenance of immune tolerance. Cancer patients, including Melanoma patients bear increased number of circulating and tumor infiltrating Treg that exert functional inhibition on tumor-specific T cells.

Temozolomide (sometimes referred to as TMZ) is an imidazotetrazine derivative of the alkylating agent dacarbazine.

Immunological factors relating to the antitumor effect of temozolomide ... appeared to suppress the frequency of CD4(+) CD25(+) regulatory T cells (Treg).
So base on the research, if activation occurs (mmune activation induced by the HD IL-2) IL-2 being a growth factor for the T-cells, will help fuel their expansion. Since the Tregs are a subset of the CD4+ T-cells, they too will proliferate.

By adding TMZ to the protocol, it suppresses the Treg function and shifts the balance tolerance toward activation of an immune response.

See the abstract at the ASCO Symposium 2010 "Ability of unsuccessful high-dose IL-2 therapy followed immediately by low-dose metronomic temozolomide to induce complete and near-complete remissions in metastatic melanoma."


Source:http://www.abstract.asco.org/AbstView_74_41534.html







“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

How therapy can teach your own immune system to fight cancer..Melanoma. Jim Breitfeller

How therapy can teach your own immune system to fight cancer

"The immune response to cancer
The immune system is our natural defense against disease. It destroys harmful bacteria and viruses that enter our bodies. In order to do this it has to recognize and label them as “foreign”. Once this happens, special types of cells in the immune system move in and destroy the invaders.

Our natural immune system can also detect cancer, because cancer cells are different from normal cells. In many cases, it will destroy these cancer cells before they turn into a detectable cancer.

Helping the immune system fight cancer
Sometimes our immune response to cancer fails and the cancer continues to grow. This can happen when cancer cells are not recognized by the immune system, or develop ways to cheat the system and escape detection. As a result, our immune system mistakes them for healthy cells and does not react.
Cancer immunotherapy aims to teach our natural defenses to identify cancer cells correctly – and then kill them.

ASCI*: a new approach that targets cancer antigens
ASCI* (Antigen-Specific Cancer Immunotherapeutics) is a new type of immunotherapy in development that targets cancer antigens and potentially destroys the cancer cells that bear these antigens. Cancer antigens are substances found on the surface of cancer cells, and are recognized as “foreign” by the body’s immune system.

ASCI* uses our own immune system to attack cancer. It does this by educating our immune system to identify and attack antigens displayed on cancer cells.
The immune system reacts towards the antigen in ASCI* – a reaction called immune response – and then attacks the cancer cells where this antigen is found."
Source:GlaxoSmithKline
http://www.immunotherapyforcancer.info/melanoma/index.shtml

There is only one major problem. Each melanoma patient has his or her own set of antigens based on their own tumors. Reseachers are trying to discover what are the major antigens that Melanoma patients exibit. For instance, MAGE-A3. There are literally thousands to choose from.

What if you get your body to produce them for you from your tumors. It sounds hard to believe but, radiation, chemotherapy with Dacarbazine plus (Patrin-2) Lomeguatrib and oblimersen sodium may help shed the right antigenic peptides. You have to get the right antigen to be presented on the dendritic cells acting as Antigen Presenting Cells (APCs) in order for the immune response to the cancer. The concentration of the antigen plays a major role in the intensity of the response.

Another problem is that you have to deplete or Block the suppressive function of the Tregs cells. This can be accomplished by lymphodepletion by preconditioning with cyclophosphamide and fludarabine or Anti-CTLA-4 blockade.

The final step of this process is the addition of interleukin-2 to activate and maintain the function of the CD8 + T-cells that mature into Cytotoxic T Lymphocytes (CTL’s). Dosing schedule and concentration of the drugs also play major role in weather an immune response is generated.



The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2




"Mike Weber was kind to forward your paper and email. It appears that you have a very good sense of, and interest in, the immune response to melanoma and to cancer in general. I believe you are right that timing of the various components of the immune response, especially with combination therapies, is important, just as it is in the orchestration of a beautiful symphony."


~ Dr. Craig Slingluff ~



Melanoma and the Magic Bullet (Monoclonal Antibodies)







Take Care,
Jimmy B

Goshen Doctor on Time's 100 List.. Melanoma ..Jim Breitfeller

Goshen Doctor on Time's 100 List

TIME Magazine announced that Dr. Doug Schwartzentruber, Medical Director of Goshen Health System's Goshen Center for Cancer Care, has been named to the 2010 TIME 100, the magazine's annual list of the 100 most influential people in the world

He is being recognized for the strides he and Goshen Center for Cancer Care are making in cancer research.


"One of the first studies to prove vaccines might have a medical benefit against cancer, Schwartzentruber's study results found the new therapeutic cancer vaccine, given in combination with an existing melanoma treatment called Interleukin-2, doubled the response rate for tumor shrinkage as well as delayed the progression of cancer in patients with metastatic melanoma."

Source:http://www.insideindianabusiness.com/newsitem.asp?ID=41419

Goshen Doctor on Time's 100 List 2010


The reason I am brining this to your attention is that I have wrote to
Dr. Schwartzentruber.

The timing of the addition of IL-2 to the vaccine is crucial to the response outcome.

Just think what could be accomplished if Dr.Schwartzentruber timed the addition of the IL-2.



The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2





Take Care,

Jimmy B

The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2..Melanoma..Jim Breitfeller

The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2

The paper that I am about to present to you is a culmination of research that was done base on my own experience as a stage IV Melanoma Patient. I wanted to know why my immune system responded and prove to myself and my doctors that it was not a statistical fluke. I dedicate this paper to all my fellow Melanoma Patients that lost their battle with the Beast, especially Bob Luker who fought so bravely but was unable to obtain Anti-CTLA-4 blockade due to the shortage proclaimed by Bristol Myer Squibb which halted compassionate drug use on 9-12-2008.

Most Melanoma tumors are accepted by the host’s immune system and progress even when they contain potentially antigenic proteins. This may be due to the tumor secreting immunosuppressive Cytokines like, TGF-Beta, IL-10, IL-4 and IL-6. TGF-β inhibits the proliferation and functional differentiation of T lymphocytes. TGF- Beta accelerates the expression of CTLA-4 by stimulated CD4+CD25– T cells. TGF- Beta requires CTLA-4 early after T Cell Activation to induce FoxP3 and generates adaptive CD4+CD25+ (Treg) Regulatory Cells. The tumor cells secrete TGF-Beta.

The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2




Take Care,

Jimmy B

New Options in Melanoma Therapy Dr John Kirkwood Feb 2010..Jim Breitfeller

Take Care,

Jimmy B

How Ipilimumab could work for You!! Melanoma.Jim Breitfeller

Pictures are from Bristol-Myer Squibb.

"If the timeline Fits, You must build it"

A Clinical Trial with this Protcol Design.


Take Care,

Jimmy B

Bristol-Myer Squibb says it will seek FDA approval for ipilimumab as a second-line treatment in advanced melanoma in 2010.Melanoma..Jim Breitfeller

Bristol-Myer Squibb says it will seek FDA approval for ipilimumab as a second-line treatment in advanced melanoma in 2010.

"Phase 3 top-line results are due from a study of ipilimumab in patients with previously untreated metastatic melanoma taking a combination of ipilimumab plus the chemotherapy dacarbazine or dacarbazine plus placebo. Concurrent with a business update to analysts and investors on Mar. 4, BMS says it will seek U.S. regulatory approval for ipilimumab as a second-line treatment in advanced melanoma in 2010, and will move the drug into Phase 3 trials in non-small cell lung cancer based on Phase 2 study data, which it would present at a major medical meeting later in 2010. The company did not provide any additional details on the data."

Source:










Bristol-Myer Squibb's Ipilimumab Can't Cure Cancer alone, It will need to be done with Combinatorial Therapy.









Take Care,

Jimmy B