A new consensus has emerged on the CD4+ helper T cell and its role in facilitating and mediating sustained anti-tumor responses. The importance of this cell population has emerged, in part due to advances in fundamental immunology and its application in cancer, as well as the massive investment in translational clinical science brought about by industry focus on the PD-1/PD-L1 class of therapeutic antibodies. The lines of evidence supporting the application of CD4+ helper T cell based therapies in clinical practice draws from several disciplines, including: histology, which has correlated overall survival with and without checkpoint inhibitors like anti-PD-1 to the presence of CD4+ helper T cells ; genomics, which has defined immune correlates in cancer genetics showing in what type of cancers CD4+ helper T cell responses are most beneficial ; and immunology, which has categorized the type of effector responses induced by T cells, showing that a polyfunctional Th1 biased response yields superior survival compared to an inflammatory Th2 response .
To date, most groups working at corralling T cell responses in oncological settings have focused on the CD8+ killer T cell, showing at times dramatic and breathtaking effect, especially in blood cancers like B-cell Lymphoma . This includes approaches utilizing monoclonal antibodies and autologous cells, such as CAR T and TCRs. One challenge with CD8+ T cells is that often, during cancer evolution and progression, one of several mechanisms are coopted to limit the ability of CD8+ T cells to control tumor cells. This includes an induced behavior in tumors, where tumor-specific CD8+ T cells become exhausted and no longer capable of exerting an anti-tumor response . CD4+ helper T cells are critical to providing the signals necessary for sustained CD8+ mediated responses . Furthermore, CD4+ helper T cells are capable of exerting direct anti-tumor activity . In sum, this is a critical population of cells whose presence not only correlates to improved responses, but also has a direct biochemical link to other important cell populations that further drive cell killing.
Within the biotechnology industry, a few organizations are working on CD4+ helper T cell-specific approaches, which can be viewed as competing technologies to LAMP-Vax. This includes autologous CD4+ T cells, such as that utilized by cell therapy pioneer Steven Rosenberg at NCI , mRNA-based MHC-II-restricted cancer antigen epitopes like BioNTech AG is using , or the neoantigen repertoire approach being pursued by Advaxis and the basis of Amgen’s license to Advaxis technology for $65M upfront and $475M in milestones . The central thesis of these programs is that activating CD4+ helper T cells will improve the quality and length of induced cancer immune responses. ITI believes LAMP-Vax offers several differentiated advantages to other approaches and has taken steps to generate data in support of these hypothesized mechanisms.
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See Xconomy’s review of CAR T and TCR trial results here, specifically noting Novartis, Juno and Kite. For initial trial reports see: (KITE PHARMA) Kochenderfer JN, Dudley ME, Feldman SA,
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(NOVARTIS/PENN) Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725-33. doi:
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*See Press Release and Advaxis’ MINE technology.