The Magic Bullet Theory for Melanoma

I think the "Magic Bullet" will be a combinatorial therapy.

It will most likely drugs strung in a sequence:

1)That make the tumor more susceptible to Chemo to shed Tumor-Specific antigens from dying tumor cells  (DTIC,Patrin-2,Cisplatin,TMZ,radiation,biochemo..etc)

2) That suppress the Tregs and help activate T-cells (Yervoy,Anti-PD-1, Anti-Gal-3 ..etc)

3) That keeps the T-cell (Cytotoxic T-lymphocytes) activated, functional and that is needed for survival. (IL-2.. etc.)

If break up the science behind T-cell actiavtion that lead to an immune response It entails not just the T-cells, but the cytockines, chemokines, Chemoattractants, the tumor’s microenvirnoment and other cells that make up the immune system’s defense.

So what do we as Patients/Oncologists need to do to orchestrate a tumor-related immune response.

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We first need the correct antigens (pieces of protein) that are related to the tumors. So, how do we accomplish this in a clinical setting? Radiation, Chemotherapy, a drug that upsets the DNA repair mechanism of the tumor cell. A necrotic mechanism of cell death was primarily involved in radiation response.

Without the correct Tumor-Specific Antigen, the T-cells don’t know where to traffic to (the Tumor Site).

Recent publications have implicated, (DTIC) Dicarbazine, (TMZ) Temozolomide with Modulators of DNA repairi. This is powerful concept for therapeutic combinations and rationale administration with DNA repair and (DDR) DNA damage response inhibitor is based on conditional (synthetic) lethality. If you can damage the outer cells of the tumor, one can generate dying cell fragments and will be processed by the macrophages. This in turn will start the presentation phase of the antigen on the Antigen Presenting Cells (APC’s).

We still have a problem. The tumors secrete suppressive cytokines and recruit the T-regulatory cells (Tregs) to the microenvironment to block any activated T-cells. This is a survival mechanism for the tumors. So the first signal is in place but the second signal is hampered by the Tregs.

i Drug resistance in melanoma: Mechanisms, apoptosis, and new potentialtherapeutic targets, Douglas Grossman1 and Dario C. Altieri21Department of Dermatology and the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA;2Department of Pathology and the Boyer Center for Molecular Medicine, Yale University, New Haven, CT, USA

DNA Repair Modulators as Anticancer AgentsYves Pommier, M.D., Ph.D.Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI-NIH, Bethesda. Tel:301-496-5944; Fax: 301-402-0752; email: pommier @nih.gov

Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferaseVincent A. Barvaux,1 Paul Lorigan,2 Malcolm Ranson,2 Amanda M. Gillum,3 R. Stanley McElhinney,4 T. Brian H. McMurry,4 and Geoffrey P. Margison1 1Paterson Institute for Cancer Research, Manchester, United Kingdom; 2Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom; 3Genta Inc., Berkeley Heights, New Jersey; and 4Trinity College, Dublin, Ireland

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In a FDA review of Oblimersen (G3139) with Dicarbazine, 2004ii the results showed no survival benefit with the addition of Oblimersen with DTIC. But, if you look at the graphs closely, there is an indication that it works but the response was being terminated with the help of the Tregs. In the first part of the graph, you see that there is a small difference, but as the timeline increased, the difference faded. This is most likely the immune response being suppressed by the Tregs in the suppressive tumor’s microenvironment. There was no blockage of the Treg function. We my own clinical experience as a patient, I only noticed an inflammation response only after I was infused with Anti-CTLA-4 at a concentration of 15mg/Kg. Was this an indication that we need Treg blockage to obtain a robust response? I am inclined to think so.

ii Genasense (Oblimersen) for metastatic melanoma. ODAC May 3, 2004. 2. FDA Review Team for Genasense (G3139)www.fda.gov/ohrms/.../ac/.../4037S1_02_FDA-Kane-Yang%20.ppt

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So once we have the right Tumor-Specific antigen, we need to activate the second signal, CD28/B7 complex. But if CTLA-4 receptor on the Treg engages with B7, the activation of the T-cell is shut down. The B7 receptors have a greater affinity toward the CTLA-4 than the CD28 molecule. This why it is necessary to use Anti-CTLA-4 Blockage, to shut down the suppressiveness of Tregs. Another receptor that can cause T-cell exhaustion is the PD-1 receptor. Tumor cells are reported to suppress the host’s immune response and escape from its immunological attack through activation of PD-1.After activation, the PD-1 receptor is upregulated gradually over time. The first appearance on the surface is in about 3-5 days and continues to populate the T-cell surface to a predetermined level. Once this happens, the activated T-cells a free to engage with the tumor cell. Once the PD-1/PD-L1 complex between the T-cell and the tumor cell is engaged, the tumor sends a signal shutting down activation.

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So, to keep the T-cells (CD4+ & CD8+) activated, one must block the CTLA-4 and PD-1 receptors.

I speculate that while manipulation of the immune system can facilitate potent T-cell responses, it will take a combinational approach, such as monoclonal antibody blockade of inhibitory immune receptors in conjunction with therapies such as radiation, radiofrequency ablation or targeted drugs including Chemotherapy to facilitate antigen release.Such an approach will eventually lead to effective and lasting immune control of tumors.

How varying the context of T cell priming alters downstream effector and memory CD8(+) T cell differentiation.http://www.immuneweb.com/wenzhai/pdf/003901.pdf

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References:

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