Early B cell recovery and CD19 antigen positive relapse
Our group has defined early B cell recovery as B cell recovery within six months of infusion, which indicates. Loss of CAR T function. Risk of relapse is considered higher with early B cell recovery due to failure of disease surveillance by circulating CAR T cells. Current therapies offered after early B cell recovery include retreatment with CAR T cells, with or without additional therapy to augment CAR T cell activity, and/or hematopoietic stem cell transplant. Limited published data exists on re-infusion for early B cell recovery with the same CAR product. Gardner et al. administered a second infusion of anti-CD19 CAR T cells to 8 patients with B-ALL who had evidence of engraftment loss. Of the eight patients, only two had CAR T cell expansion after re-infusion; however, the six patients who did not respond to the re-infusion of CAR T cells did not receive what most consider now to be the standard lymphodepleting preparatory chemotherapy regimen prior to their retreatment54. In the CTL019 trial, 17 of 55 patients were received repeat infusion of murine CTL019 for poor persistence at 3 and/or 6 months after initial infusion. Reinfusion induced B cell aplasia for a second time in 1 of 7 children treated for B cell recovery, while 6 of 7 patients reinfused for CD19 positive hematogones demonstrated continued B cell aplasia six to 21 months after repeat infusion. Of this group, 6 remained in remission 9 to 24 months after initial infusion, and one experienced CD19 negative relapse70. Methods being tested to improve success rates of CAR persistence after re-infusion include concurrent treatment with PD-1 checkpoint inhibitor and infusion of different CAR constructs such as humanized CD19 CARs to overcome immune-mediation rejection of murine-derived anti-CD19 CARs. At our center, concurrent treatment with programmed death-1 (PD-1) checkpoint inhibitor in those with early CAR T cell loss/no response to CAR T cell therapy has shown encouraging results. Fourteen patients received pembrolizumab or nivolumab, and three of six patients who received pembrolizumab for early B cell recovery re-established B cell aplasia. Two of these patients had persistent B cell aplasia with ongoing pembrolizumab therapy71.
Treatment for antigen positive relapse with further CAR T is possible, since the CD19 antigen is still expressed. Lee et al. described 3 patients who received re-infusion of CAR product with a CD28 endodomain for recurrent CD19+ disease, but none had an objective response47. In the phase 1 CTL119 (humanized CD19 scFv) trial, 6/9 patients treated with CTL119 CAR for relapse after prior CD19 CAR T therapy achieved MRD negative CR72. Work is ongoing to assess whether immunogenicity of the murine CAR plays a role in such events, which might be alleviated by a humanized CAR. Despite the different CAR constructs, lack of CAR-specific T cell responses in such patients suggest a possible mechanism of immune-mediated rejection upon repeat dosing. In very early data testing the addition of a checkpoint inhibitor to CAR T therapy resulted in 2 partial and 2 complete responses 71.