Research is Paying off!!!!!! Adoptive Cell Transfer Therapy. Jim Breitfeller

Adoptive Cell transfer Therapy.

I am reading a paper by Dr. Rosenberg on Adoptive Cell transfer Therapy.
See, That was one of my paths that I wanted to go down but I Had the wrong blood type. Mine was HLA-A2 Negative they (Rosenberg) was looking for patients of HLA-A2 positive so I was not a match for the trial. That was on 12/13/05. So I never did the research because I was the wrong type. Well, I am working with another patient that asked me to take a look at this therapy. And Now the pieces are starting to come together.

TIL with a lymphodepleting preparative regimen

"Several methods had been established for the generation of tumor antigen-reactive lymphocyte cultures and evaluated in clinical trials. However, highly cultured, highly expanded cloned lymphocytes lacked potency in vivo. Although bulk TIL could mediate objective clinical responses, they were often of short duration and the bulk TIL were logistically difficult to grow9. Because it had been established that a non-myeloablative conditioning regimen could be safely administered in conjunction with adoptive T-cell transfer and IL-2 in patients with metastatic melanoma, we next evaluated whether highly selected, tumor antigen reactive, bulk TIL populations that were rapidly expanded could mediate anti-tumor responses. In an initial cohort of 13 patients22, our results were markedly different than those seen after administration of cloned lymphocyte cultures. This approach resulted in the persistent repopulation of anti-tumor T cells in the cancer patients, with proliferation of functionally active transferred cells in vivo and traffic to tumor sites. This led to regression of the metastatic melanoma in six of 13 patients as well as the onset of autoimmune melanocyte destruction in some patients.

This initial cohort of patients was followed with accrual of additional patients. We reported the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of 35 patients with refractory metastatic melanoma23. All but one of these patients had disease that was refractory to treatment with high-dose IL -2 and 18 had progressive disease after chemotherapy. Patients underwent non-myeloablative lymphodepleting conditioning with cyclophosphamide and fludarabine, followed by cell infusion with autologous tumor-reactive, rapidly expanded TIL cultures and high-dose IL-2 therapy. Eighteen treated patients (51%) experienced objective clinical responses by RECIST criteria, including three complete responses that are ongoing more than three years after treatment. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Although the toxicities of treatment were acute and severe, including the expected toxicities of high-dose IL-2 therapy and the hematologic suppression of chemotherapy, most toxicities were transient and resolved within two weeks. These results suggested that lymphodepleting chemotherapy followed by the transfer of highly avid anti-tumor lymphocytes could mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma. Table 2 shows the patients who responded to this treatment, along with the duration of their response as of May, 2007, and the initial sites of disease."

Thank You Dr. Roesenberg!!!!!!!!!!!!!!!!!!



CR= complete response
PR= partial response

Questions that need to be answered:

1)Were they all HLA-A2?

2) what blood type? O, A ab...?

3) What type of Melanoma? ( Nodular,Superficial spreading,Lentigo maligna and Acrallentiginous melanoma


TYPES OF CUTANEOUS MELANOMA

There are four pathologic types of cutaneous melanoma each with a characteristic growth pattern. (1) Superficial spreading melanoma is the most common type, accounting for 70% of all cases. This type typically arises from a pre-existing nevus and expands in a radial fashion before it enters a vertical growth phase. (2) Nodular melanoma, a more aggressive tumor, accounts for approximately 15 to 30% of cases. This lesion arises de novo from normal skin and has no radial growth phase. It is found more commonly in males. (3) Lentigo maligna melanoma accounts for less than 10% of cases. This type of lesion is found more commonly in females and the elderly population. The lesions are typically large and flat, follow an indolent growth course, and rarely metastasize. (4) Acrallentiginous melanoma also accounts for less than 10% of lesions, but occurs in a higher proportion (35 to 60%) of nonwhite patients.


SEE NOW WE KNOW TWO PATHS BUT ARE VERY SIMILAR,

Rosenberg
Genetically alters some cells and reintroduces them to stimilate the T cell, to create Signal # 1 and the IL-2 is there to do the cell to cell communication (signal #2)

Kirkwood
Uses CTLA-4 Blockage to stimulate the T Cell to create signal # 1 and the IL-2 is there to do the cell to cell communication (signal #2)

This first interaction involves the CD4 or CD8 proteins which form a complex with the CD3 protein to bind to the MHC molecule of the (APC). Antigen-presenting cell This is also called "Signal 1" and its main purpose is T cell activation.



However, this is insufficient for producing a T cell response by itself.

In fact, lack of further stimulatory signals sends the T cell into anergy. Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances.



The Second costimulatory signal necessary to continue the immune response can come from B7-CD28 and CD40-CD40L interactions. The primary role of the B7 proteins is to give a second signal to the T cell.

The B7 protein/receptor is present on the Antigen-presenting cell and is able to interact with the CD28 receptor on the T cell surface; this is also known as "Signal 2". There are other activation signals which play a role in immune responses.

On these T cells there is are family receptors whose job is downregulate the T cell activation so the immune system maintains metabolic equilibrium so the immune system doesn’t start an autoimmune response and cause it to attack itself. One of these receptors is Cytotoxic T lymphocyte-associated antigen (CTLA4).


It was also shown that the anti-CTLA-4 antibodies had a greater affinity to CTLA-4 than the B7 receptor. So by doing the CTLA-4 Therapy, it allowed signal 1 to become active.



So in the presents of the CTLA-4 antibody Therapy, I my case, we may have extended the antitumor response of the T-cells. This left Signal 1 active.



We then, hit the immune system with High dose of IL-2. This must have stimulated the cell to cell communication (Signal 2) causing the immune response to kick in against the foreign molecule (The Tumor)


It is important to know your Blood Chemistry!!!!!!!!!!!!!

Your blood chemistry will lead you down the right path!!!!!!!!!!!!!!!

I also believe that we need to be carefull on how the protcol is set up.

I have read that the combo CTLA-4 and the IL-2 had the same response as the IL-2 alone.

I think it is because they were flooding the # 2 signal cell to cell) and drowning out the T cell Activation. It is like two wave fuctions coming together. If they are in perfect harmony, they will build off of each other and double. If they come at each other at the other 180, the wave will be cancelled out. Something like Sonar.


This just my Hypothesis.

They is probably alot more Biochemistry going on than how I explained it.

But I am not a Biochemist.


Jimmy B