Abstract
Background
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 and relapsed 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 et al., Blood 2011). While the anti-tumor activity of the CD19-targeted CAR-modified (CAR+) T cells has been modest in the setting of rapidly progressive and chemotherapy refractory disease, we have observed significantly increased rates of durable responses in CLL patients with reduced disease burden and chemotherapy-sensitive disease (Park JP et al., ASH Abstract 2011). In order to address the previously recognized limitation of CAR+ T cells in the setting of advanced disease, we designed a phase I clinical trial wherein previously untreated CLL patients with residual disease following the first-line chemotherapy will receive the CD19-targeted CAR+ T cells as a consolidative therapy.
Patients and Methods
Patients with previously untreated CLL with high-risk disease features as defined by the presence of unmutated IgHV, del11q or del17p received the first-line therapy consisting of 6 cycles of pentostatin, cyclophosphamide and rituximab (PCR). Patients who have achieved either partial response (PR) or complete response (CR) with detectable minimal residual disease (MRD) were enrolled to the trial and underwent leukapheresis. Autologous T cells collected by leukapheresis were transduced with a retroviral vector encoding the anti-CD19 scFv linked to CD28 co-stimulatory and CD3ζ signaling domains. Patients received cyclophosphamide conditioning therapy followed two days later by the infusion of the CAR+ T cells in 3 dose-escalating cohorts. Response assessment was performed according to the criteria established by the NCI-WG. Serial bone marrow aspirate and blood samples were assessed for the modified T cell persistence (assessed by flow and RT-PCR) and cytokine profile analysis
Results
To date, 8 patients have been enrolled and 6 patients received the CAR+ T cells, completing the two dose cohorts of 3x106 and 1x107 CAR+ T cells/kg (3 in each cohort). The median age was 61.5 years (range, 45 – 68). 6 pts had unmutated IgHV and 2 pts had del11q. Median follow-up from the time of T cell infusion was 7 months (range, 2 – 12 mos) at the time of this report, and the median time from the completion of the upfront PCR chemotherapy to the T cell infusion was 6.5 mos (range, 4 – 12 mos). No DLT was observed. Cytokine release syndrome (CRS) was observed in 2 patients as manifested by fever, nausea, anorexia and transient hypotension, and none required steroid or other anti-inflammatory agents. There was a positive correlation between the development of CRS and the modified T cell persistence. 2 patients who had PR following the first-line PCR chemotherapy achieved CR after the T cell infusion; 2 patients maintained PR; and 2 patients had progressive disease (PD). Of the 2 patients with PD, one achieved PR after 6 cycles of PCR but had progressive lymphocytosis with ALC doubling time of 1 month at the time of T cell infusion and the other patient relapsed in lymph node only while the marrow remained MRD negative.
Conclusions
The infusion of autologous CD19-targeted CAR+ T cells appears to be safe and has demonstrated promising anti-tumor efficacy to further improve CR rates in patients with high-risk CLL undergoing the first-line purine analog-based chemotherapy. While the number of treated patients is too small to draw a definitive conclusion, our findings suggest that the second-generation CD19-targeted CAR+ T cells has enhanced anti-tumor activity in patients with reduced disease burden and is more effective in eradicating disease in the marrow versus lymph nodes. Enrollment is ongoing to this study, and updated clinical and correlative data will be presented.
Disclosures:
No relevant conflicts of interest to declare.
Autologous CD19-Targeted CAR T Cells in Patients with Residual CLL following Initial Purine Analog-Based Therapy