Patient T cells may be genetically modified to express chimeric antigen receptors (CARs) targeted to antigens expressed on tumor cells. We have previously reported initial results from a phase I clinical trial treating patients with chemotherapy refractory chronic lymphocytic leukemia (CLL) with autologous T cells modified to express the 19–28z CAR targeted to the CD19 antigen expressed on most B cell malignancies (Brentjens RJ, Rivière I et al., Blood, 2011;118(18):4817-28). In the previous reported cohorts of 8 patients, CAR-modified T cells were infused in the setting of rapidly progressive and chemotherapy refractory disease. Although prior conditioning therapy with cyclophosphamide enhanced in vivo persistence of the modified T cells, all patients had cyclophosphamide-resistant disease and none experienced objective remissions or significant hematologic recovery. We hypothesized that suboptimal clinical response observed in the study was because of a large tumor burden at the time of T cell infusion and refractoriness to conditioning therapy. On the basis of these findings, we have modified the protocol to allow prior cytoreductive therapy and conditioning with chemotherapeutic agents based on predicted chemosensitivity.
Since these protocol modifications, two patients have been treated. Both had relapsed disease with unfavorable disease phenotype following previous treatments with various chemotherapy and biologic regimens. Of the two patients treated to date, one achieved partial remission (PR) and the other attained minimal residual disease (MRD)-negative complete remission (CR) according to standard international criteria. The first patient experienced reduction in peripheral lymphocytosis and obtained stable disease with persistent anemia and thrombocytopenia after two cycles of bendamustine and rituximab (BR). Following the bendamustine conditioning and modified T cell infusion, PR was achieved with complete hematologic recovery, lasting for more than 8 months at the time of this report. The second patient achieved PR following two cycles of BR and subsequently attained MRD-negative CR with concomitant development of B cell aplasia after receiving the bendamustine conditioning and CAR-modified T cells. At the time of this report, the response has been sustained for more than 5 months. Notably, this patient has long-term persistence of the CAR-modified T cells, detected at 12 weeks following the T cell infusion. No significant toxicities were observed in the two patients, except for fevers lasting 3–4 days and transient grade 2 hypoxia. While the number of treated patients on the revised protocol is too small to draw a definitive conclusion, our findings of a significant improvement in the degree and depth of response with the bendamustine conditioning compared to our previous cohorts of cyclophosphamide-refractory CLL who received cyclophosphamide as their conditioning suggest a potentially greater effect of conditioning regimens through tumor burden reduction than the induction of a supportive cytokine response or lymphocyte depletion. In light of these initial observations, the role of the conditioning chemotherapy regimen given prior to adoptive T cell therapy needs to be carefully evaluated since not all regimens may ultimately be equally effective with respect to clinical outcomes.
Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Asterisk with author names denotes non-ASH members.