The magic bullet theory for melanoma


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The magic bullet theory for melanoma

  1. 1. The Magic Bullet Theory for MelanomaI 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 thatmake up the immune system’s defense.So what do we as Patients/Oncologists need to do to orchestrate a tumor-related immune response. 1
  2. 2. 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 thatupsets the DNA repair mechanism of the tumor cell. A necrotic mechanism of cell deathwas 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 withModulators of DNA repairi. This is powerful concept for therapeutic combinations andrationale administration with DNA repair and (DDR) DNA damage response inhibitor isbased 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 inturn 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 asurvival mechanism for the tumors. So the first signal is in place but the second signal ishampered by the Tregs. In a FDA review of Oblimersen (G3139) with Dicarbazine, 2004ii the results showed nosurvival benefit with the addition of Oblimersen with DTIC. But, if you look at the 2
  3. 3. graphs closely, there is an indication that it works but the response was being terminatedwith the help of the Tregs. In the first part of the graph, you see that there is a smalldifference, but as the timeline increased, the difference faded. This is most likely theimmune response being suppressed by the Tregs in the suppressive tumor’smicroenvironment. There was no blockage of the Treg function. We my own clinicalexperience as a patient, I only noticed an inflammation response only after I was infusedwith Anti-CTLA-4 at a concentration of 15mg/Kg. Was this an indication that we needTreg blockage to obtain a robust response? I am inclined to think so.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 activationof the T-cell is shut down. The B7 receptors have a greater affinity toward the CTLA-4than the CD28 molecule. This why it is necessary to use Anti-CTLA-4 Blockage, to shutdown the suppressiveness of Tregs. Another receptor that can cause T-cell exhaustion isthe PD-1 receptor. Tumor cells are reported to suppress the host’s immune response andescape from its immunological attack through activation of PD-1.After activation, the PD-1 receptor is upregulated gradually over time. The firstappearance on the surface is in about 3-5 days and continues to populate the T-cellsurface to a predetermined level. Once this happens, the activated T-cells a free to engagewith the tumor cell. Once the PD-1/PD-L1 complex between the T-cell and the tumor cellis engaged, the tumor sends a signal shutting down activation. 3
  4. 4. So, to keep the T-cells (CD4+ & CD8+) activated, one must block the CTLA-4 and PD-1receptors.I speculate that while manipulation of the immune system can facilitate potent T-cellresponses, it will take a combinational approach, such as monoclonal antibody blockadeof inhibitory immune receptors in conjunction with therapies such as radiation,radiofrequency ablation or targeted drugs including Chemotherapy to facilitate antigenrelease.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 memoryCD8(+) T cell differentiation. 4
  5. 5. References: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, NewHaven, CT, USADNA 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.govSensitization of a human ovarian cancer cell line to temozolomide by simultaneousattenuation 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, Irelandii Genasense (Oblimersen) for metastatic melanoma. ODAC May 3, 2004. 2. FDAReview Team for Genasense (G3139) 5