I recently had the honor to participate in several sessions at the IO360 conference in New York. While on a panel about combining Immuno-Oncology agents and the role of diagnostics, I began to extemporaneously lay out some observations that I had not formally voiced altogether. These "binary strawmen" were in part a response to discussion around the categorization of "IO" and "Non-IO" as we often call them in our analytics. I had given a talk the day previous to this panel where I provided some key observations around programs in development, deals and financings predicated on MOAs and making this clearly artificial distinction. While probably anything that works against cancer is dependent on the role of the immune system, directly or indirectly per the MOA, the binary labeling can be useful for analyzing trends and isn’t entirely a false dichotomy. And so on this panel I began to talk about three big picture strawmen, again as binaries, to make a point.
Firstly, that the heterogenous and evolving cancer demands a therapeutic approach that is as adaptable as it is, noting this heterogeneity is spatial (across the tumor, between primary and metastatic sites) and over time. Hence, the immune system, being as plastic and diverse as the cancer, must be the most potent adversary we can harness against a tumor.
Secondly, that in thinking about therapies and diagnostics, we seem at times caught in a reductionist mode, focused on a single target, like PD-1/PD-L1, whereas a holistic perspective and approach would likely be more valuable: thinking of interacting and redundant pathways, orthogonal MOAs and therapeutic modalities, or about multi-analytes and signatures versus a single entity like PD-L1 expression.
Thirdly (and not exhaustively, as there are certainly more dualities to be commented on), I raised the point about the increasingly interesting and relevant distinction between therapeutic approaches that are endogenous versus exogenous. That is, delivering a checkpoint inhibitor plus perhaps other biologics like a cytokines and even small molecules that counter the cancer’s immunosuppression, stimulate the immune system’s anticancer activity, and ultimately engage targeting of antigens including neoantigens to eliminate the cancer wherever it may be lurking including micrometastases. On the other hand, many are directing their efforts at elegantly constructing exogenous systems to target the tumor, such as highly engineered CARTs or Oncolytic Viruses which hopefully when administered to the patient do the heavy lifting of killing the tumor. Of course, this is again a bit of a false dichotomy as it may still be necessary for such approaches to invoke the endogenous immune system to obtain the final eradication as to enable immunosurveillance against any dormant or quiescent tumor cells.
One final point is, as we have been discussing at Defined Health, now Cello Health BioConsulting, and which Dan Chen made an impassioned speech about at Rational Combinations last Fall (a sister conference to IO360), we are also seeing an increasing trend towards advanced engineering of therapies, complex biologics whether multifunctional antibodies or cell therapies, that do many things, like hitting several targets, that are controllable, etc. But maybe we’ll save this discussion to another post!