TCR Activation Impact On Chimeric Antigen Receptor Therapy Against Acute Lymphoblastic Leukemia
Tremendous progress has been achieved employing immunotherapy for B cell acute lymphoblastic leukemia (ALL), the most common diagnosis in children with cancer and a leading cause of cancer-related death. Recent trials using transfer of autologous T cells genetically modified to express chimeric antigen receptor T cells (CAR T) targeting the B cell restricted antigen CD19, have demonstrated remission rates of 80% in relapsed or refractory ALL. The feasibility of this therapy depends on the ability of the CAR T cells to expand following adoptive transfer, not always possible in this heavily pre-treated patient population. In these instances, allogeneic donors may be an alternative source to produce CAR T, however there is little known about the effectiveness of allogeneic CAR T cells (alloCART). These alloCART would have specificity for two antigens, one being the CAR target and the other derived from the endogenous T cell receptor (TCR) that could have reactivity against alloantigens. The impact of the endogenous TCR could potentially impact the efficacy of the alloCART against tumor and has not been well studied. We established a murine model to specifically evaluate the biology of alloCART and, more generally, the biology of CAR T cells encountering TCR antigen. Using gender mismatched CART cells derived from female donors to treat male recipients, we found significantly lower survival due to poor leukemia clearance compared to gender matched female recipients. We then controlled for TCR specificity of CAR T cells using TCR transgenic CD4 or CD8 T cells targeted against male histocompatibility antigens, and found that concurrent CAR and TCR stimulation induced a 6X reduction in CART numbers, an increase in T cell exhaustion markers (PD-1, Tim3, and Lag3) and 5X increase in apoptotic CAR T cells in the bone marrow compared to CAR stimulation in the absence of TCR antigen. The negative effects of the active TCR was predominantly in CD8 T cells. Surprisingly, CD4 T cells, by dogma non-cytolytic, acquire cytolytic capabilities through CAR activation, were able to clear leukemia without CD8 T cells and were less susceptible to concomitant TCR activation. Indeed, the presence of TCR and CAR antigens led to increased CD4 CAR T expansion, and better persistence than observed with CD8 CAR T. In addition, CD4 CAR T cells produced higher levels of IL2, IFN, and TNF compared to CD8 T cells. These findings suggest that CD4 CAR T may have advantages over CD8 CAR T cells, particularly when TCR antigen may be present such as with the use of allogeneic donor cells. Future work will seek to examine the downstream pathways in TCR vs. CAR and effects of TCR elimination.
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