Brain cancers are particularly challenging foes because they often (i) present with heterogeneous populations of cancer cells; (ii) have low overall mutational burdens; (iii) do not display many actionable therapeutic targets; and (iii) tend to exist in a TME that is populated with strongly immunosuppressive cells. These factors must be taken into account when advancing effective therapeutic approaches.
For these reasons, one of the most promising avenues of brain tumor research involves immunotherapies designed to harness the human immune system, and focus its unique cytotoxic weaponry on selectively eliminating cancer cells. One of the laboratories leading the development of immunotherapies for brain tumors is that of Michael Lim, MD (Professor and Chair of the Department of Neurosurgery at Stanford University; see here and here).
We first met Mike a few years ago at a reception during the Society for Neuro-Oncology Annual Meeting. The talk quickly turned to the science of designing and developing immunotherapies for brain tumors, and the significant barriers to implementing such immunotherapies in the clinic. For Episode 7 of the Brain Cancer Science Talk series, Mike and I decided to share some of our thoughts with the MissionGBM audience regarding:
Characteristics of effective immunotherapies regardless of modality
Discovering and developing actionable biomarkers for patient selection and enhanced Objective Response outcomes
Encouraging tumor-specific cytotoxic T lymphocytes and other anti-cancer immune cells to activate and traffic to the tumor site in the brain; and
Sustaining specific anti-cancer immune responses in a highly immunosuppressive TME.
In addition, we touch on a few fundamental scientific limitations that have plagued more rapid advancement of promising immunotherapies into the clinic, including:
Lack of high quality pre-clinical models that translate to the human clinical environment; and
Neuro-Oncology’s historical neglect of rigorous neuropharmacology studies for therapeutic candidates, thus often leading to an inability to interpret clinical trial data.
We conclude by focusing on accelerating the clinical development of immunotherapies (i) by deploying Window of Opportunity trial designs to directly obtain the missing neuropharmacology and treatment response data in the best model system possible (the actual human); (ii) by highlighting the promise of adaptive platform trial designs using rigorously vetted clinical candidates; and (iii) by emphasizing the need for modernization of the Regulatory framework to permit clinical trial designs that will be necessary to register effective new therapeutic agents in a rare disease area such as brain cancers.
It is clear from #Data generated by multiple, independent research programs that immunotherapy approaches to treat brain tumors are converging on a manageable set of mechanistic pathways that ought to drive material advances in the availability of new treatment options for brain cancer patients over the next decade. The capital is available; it is time for the science to create investable opportunities. Count us optimistic.
