By Colin Magowan
A new interest has emerged on the CD4+ helper T cell and its role in anti-tumor responses. This renewed focus on the importance of this cell population is in part due to advances in the fundamental understanding of 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 evidence supporting the role of CD4+ helper T cells 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 in tumors; genomics, which has defined immune correlates with cancer genetics, showing some types cancers where CD4+ helper T cell responses are most beneficial; and immunology, which has increasingly been able to precisely categorize the type of responses induced by T cells, for example, showing that a polyfunctional Th1 biased response can improve survival compared to an inflammatory Th2 response.
To date, most in oncological settings have focused on the CD8+ killer T cell, for example, reprogramming them to kill tumor cells and showing at times dramatic effects in early clinical studies, especially in blood cancers like B-cell Lymphoma. These include approaches utilizing monoclonal antibodies and engineered autologous CD8+ T cells, such as CAR T and TCR transduced cells for adoptive cell therapy. These approaches show significant promise, but may not be the end-all be-all. For example, 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. However, ITI technology could potentially boost antigenspecific CD8 T cell response via cross-priming in tumor settings.
Further, CD4+ helper T cells are critical for providing the signals that are needed for sustained CD8+ mediated responses. Furthermore, some have found that CD4+ helper T cells are capable of exerting direct anti-tumor activity. In sum, this is a critical population of immune cells whose presence not only correlates to improved responses, but also has a direct 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, the company who inked a $1.5 billion deal with Sanofi and another deal with $310 million in upfront payments from Genentech in 2016 , 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 . A central thesis for these programs is that activating CD4+ helper T cells will improve the quality and length of induced cancer immune responses. Their significant traction in the recent years validates the relevancy of our platform, and that Immunomic is now focusing on the right space at the right time.
Immunomic Therapeutics believes that the LAMP-Vax platform offers several differentiated advantages to these other approaches. We feel that we may have one of the only ways of directly trafficking antigens into the MHC-II compartment for direct, antigen specific activation of CD4+ T cells. In 2016, we quickly pivoted, focusing on building our expertise and capabilities in R&D, process development, and early clinical development to support applying LAMP-Vax in the cancer immunotherapy arena, where its proposed mechanism is extremely relevant today. We have taken steps to generate data in support of these hypothesized mechanisms. On the heels of the Astellas deal, we feel that a potential future partnership in the oncological arena is imminent.