Why indeed? Though there’s no clear-cut answer yet, CAR-T’s current catalog of success might itself help explain why it’s not very effective against solid tumors.
- In humans, CAR-T, i.e. chimeric antigen-receptor bearing T cells, have been shown effective against CD19+ B cell tumors.
- Directly interacting with B cells is part of the evolutionary mandate of CD4 T cells. B cells depend on CD4 T cell help, i.e. specific and precise instructions from CD4 T cells that guide them in performing their effector functions. So CAR-T cells’ effectiveness against B cell tumors likely piggy-backs on evolutionarily conserved CD4 T cell-B cell interaction capabilities, T cell membrane-bound anti-CD19 antibody expression notwithstanding (1; mouse model study).
- OTOH, CAR-T CD4 Tcells don’t necessarily interact directly with other cell types as a matter of course. A priori, CAR-T CD4s likely don’t express molecules that enable interactions with non-B cells such as solid tumors.
- CAR-T CD4s’ interactions with non-B cells such as solid tumors may require intermediary cell types such as APCs (antigen-presenting cells) that deliver precise instructions to turn on specific genes and express specific molecules necessary for CAR-T CD4s to stably and effectively engage non-B cells.
- In the absence of such mediation, CAR-T CD4-solid tumor interactions may remain transient and hence non-effectual, even when those CAR-Ts express a membrane-bound anti-tumor antibody. Such ineffective anti-solid tumor CAR-T CD4s may render ineffectual anti-solid tumor CAR-T CD8s as well.
- In the case of solid tumors, physical barrier is another obstacle. CAR-Ts might not stably express the requisite and specific metalloproteases and other enzymes that break down a particular tumor’s unique extracellular matrix. In other words, if not artificially endowed with such capacity, CAR-Ts might not even effectively make their way into solid tumor tissue (2; mouse model study). A consideration that’s superfluous for CAR-Ts acting against B cell tumors.
- Long, Adrienne H., et al. “4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors.” Nature medicine (2015).
- Caruana, Ignazio, et al. “Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes.” Nature medicine 21.5 (2015): 524-529.