CAR T Cell Therapy for Acute Lymphoblastic Leukemia: An Evolutionary Perspective
Enthusiasm for the CAR T cell approach may redirect rather than augment other possibly safer, more effective, evolutionarily informed approaches to cancer therapy.
A US Food and Drug Administration (FDA) panel recently recommended the approval of CTL019 chimeric antigen receptor (CAR) T cell therapy for acute lymphoblastic leukemia (ALL). This first-ever recommendation for a CAR T therapy was based on evidence that the treatment's clinical benefits outweighed considerable safety concerns.1,2 The population eligible for this therapy is restricted to children through young adults with relapsed or refractory B cell ALL, among whom the survival rate can be less than 30%.3
CAR T cells have engineered receptors comprised of a cell-surface component that binds to a tumor antigen and is attached to one or more internal signal initiators. CTL019 CAR T cells are designed to identify ALL B cells by the CD19 cell surface protein also expressed on normal B cells.
By design, CAR T cells circumvent major histocompatibility complex (MHC) presentation and thus the pathways to this mechanism of immunological activation. The genetically modified receptor aboard these cytotoxic T cells binds directly with a tumor antigen to initiate cell killing. This approach necessitates CAR T cell interaction with a specific surface molecule, which will often be a self-antigen found on normal and cancer cells.
In childhood ALL that does not respond to standard therapy, the risk of CAR T killing normal cells must be weighed against the probability of death from the cancer itself. For ALL an alternative therapy is life-long immune suppression following hematopoietic stem cell transplant (HSCT). The potential for destruction of normal B cell populations by CAR T cells may therefore be considered an acceptable risk.
It is, however, important to recognize that years of experience titrating immune suppressive drugs to prevent graft-versus-host disease after HSCT may minimize the risk to the surviving patient, whereas, at this time, CAR T cells cannot be withdrawn, and deleterious effects of B cell depletion may differ from patient to patient.
CAR T cells are sometimes referred to as a “living drug” because their action directs a therapeutic molecule against a cellular target. From an evolutionary perspective this term is apt because, like an antimicrobial drug favoring the evolution of antimicrobial resistance, CAR T cells can favor evolution of resistance through selective pressure on an antigen. This evolutionary effect has already been noted in response to CTL019: subpopulations of tumor cells altered CD19 have emerged during treatment, resulting in patient relapse.4