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.