CAR-T cells and checkpoint inhibitors are currently the two major approaches to ‘turbocharge’ the immune system to fight cancer. While current generation of CAR-Ts have been found to work fairly well for blood cancers, especiallycancers, I’ve argued elsewhere ( ) this could well be because such approaches piggy-back on evolutionarily conserved mechanisms for T cell-B cell interactions which are the backbone of proper function. However, such results haven’t yet been achieved for solid tumors where such approaches remain largely non-tumor specific, a major liability since it leaves open the possibility of fulminant tissue pathology and even autoimmunity.
In that respect, these two approaches aren’t necessarily an improvement on current cancer therapy mainstays, radiation and chemotherapy, both of which come with the well-known price tag of considerable collateral tissue damage. For example, CAR-Ts are increasingly hitting roadblocks in the form of life-threatening complications and even deaths in clinical trials and that too for other blood not even solid tissue cancers, so much so that leading cancer immunotherapy biotech,, recently mothballed its lead CAR-T therapy, for ALL ( ) ( ).
As-yet unattained, singular promise ofis potential to specifically target tumors, using tumor antigen-specific approaches. Major obstacles in achieving this goal remain
- Identifying and validating tumor-specific antigens for various cancers.
- Identifying, isolating and in vitro expanding tumor antigen-specific T cells, both CD4 and CD8.
- Confirming tumor antigen-specificity of such T cells.
Steps 1 and 2 are extremely technologically challenging in basic immunological research itself so likely even more so in human immunology. As technological capabilities to a) identify tumor-specific antigens, and b) manipulate human T cells in vitro improve, chances of achieving a theoretical no-pain-all-gain goal could improve. Only such an approach would optimally harness the unique antigen-specific capacity of the adaptive immune system to specifically target and eliminate tumors without damaging normal tissues. A 2015 review () by Ton Schumacher and is one of the most comprehensive in contextualizing the scope and potential of such as-yet unrealized tumor antigen-specific immunotherapy.
However, such an approach would likely still remain rather labor-intensive and artisanal since it’d remain individualized, personalized if you will. For one, mutations within tumors are increasingly recognized to be very idiosyncratic, varying not only from one patient to another but also from one part of a tumor to another. For another, as we already know from transplantation, T cell capacity fornecessitates autologous T cell infusions for cancer Rx ( ).
2. Xconomy, Alex Lash, March 1, 2017.
3. Schumacher, Ton N., and Robert D. Schreiber. “Neoantigens in cancer immunotherapy.” Science 348.6230 (2015): 69-74.