January-February 2015, Volume 12, Issue 1
CAR T Cells in Acute Lymphoblastic Leukemia
Published on: January 13, 2015
After decades of work, the last two to three years have brought about a successful translation of basic immunology that gave rise to two promising strategies to modify the immune system to treat cancer. One approach involves antibodies targeting immune checkpoints, CTLA-4 and PD-1, to release the brake on T cells to attack tumor cells. Another strategy involves infusion of T cells genetically modified to express a chimeric antigen receptor (CAR) to target a specific tumor antigen. While immune checkpoint inhibitors gained their first clinical success in solid tumors, CAR T cells first emerged as a promising therapy in hematologic malignancies after several clinical trials demonstrating unprecedented clinical activity of CD19-targeted CAR T cells in patients with relapsed/refractory acute lymphoblastic leukemia (ALL).
In 2013, investigators from Memorial Sloan Kettering Cancer Center (MSKCC), the University of Pennsylvania, and the National Cancer Institute simultaneously reported complete remission (CR) rates ranging from 71 percent to 85 percent in a total of 23 pediatric and 17 adult patients with relapsed/refractory ALL, using slightly different versions of CD19-targeted CAR T cells.1-3 Subsequently, in 2014, the same group of investigators published the updated results from respective phase I clinical trials, confirming the excellent response rates and durability of response in a larger group of patients.
Dr. Marco Davila and colleagues from MSKCC reported a CR rate of 88 percent in 16 adult patients with relapsed/refractory ALL using retrovirally transduced CD19 CAR T cells with the CD28 costimulatory domain.4 At the 2014 ASH Annual Meeting, we presented updated data on behalf of the MSKCC group, reporting the outcome of 27 adult patients evaluable for response.5 Thirty percent of patients had prior allogeneic transplantation, and the median age of the patients was 55 years (range, 23-74 years), which is significantly older than that of published clinical trials in adult ALL patients using conventional chemotherapy (e.g., 31-34 years). A CR rate of 89 percent was observed in this larger cohort, regardless of the disease risk characteristics. At a median follow up of six months (range, 1-38 months), 12 patients remained disease-free including seven without subsequent allogeneic transplantation. Significant cytokine release syndrome (CRS), defined as requiring vasopressors for hypotension or mechanical ventilation for hypoxia, and grade 3/4 neurotoxicities (e.g., encephalopathy, aphasia) were observed in 18 percent and 25 percent of the patients, respectively. Considering the CR rates of 20 to 37 percent with conventional chemotherapy and 43 percent with the recently approved bispecific antibody blinatumomab6 in a similar adult patient population with relapsed ALL, the reports by Dr. Davila and by Dr. Park and colleagues confirm CD19 CAR T cells as a promising therapy and support their further exploration in adult ALL patients.
Similar clinical activity has also been demonstrated in pediatric patients with relapsed ALL by two groups. Dr. Shannon Maude and colleagues from the University of Pennsylvania reported a CR rate of 90 percent in 25 pediatric and five adult ALL patients, using a lentivirally transduced CD19 CAR with 4-1BB as the costimulatory domain,7 and Dr. Stephan Grupp’s group updated the data at the 2014 ASH Annual Meeting.8 The median age of all patients was 14 years (range, 5-60 years), and durable responses were noted with 67 percent six-month event-free survival as well as the long-term persistence of CAR T cells. However, the T cells persisted longer in pediatric patients, as only one of the five adult patients in the study had T cells lasting beyond three months, suggesting potential differences in pediatric and adult patients. Severe CRS and self-limiting neurotoxicities were observed in 27 percent and 43 percent of the patients, respectively. Dr. Daniel Lee and colleagues from National Cancer Institute reported a CR rate of 70 percent in 20 pediatric patients with relapsed ALL in their intention-to-treat analysis, using a retrovirally transduced CD19 CAR with the CD28 costimulatory domain.9,10 Compared with the report from the University of Pennsylvania, more patients proceeded to allogeneic transplantation after achieving CR following CAR T-cell therapy, limiting the analysis and direct comparison of CAR T-cell persistence between the two studies.
While all three studies consistently highlight the potent clinical activity of CD19-targeted CAR T cells in ALL, these trials vary significantly with respect to the costimulatory domains in the CAR construct (CD28 vs. 4-1BB); means of gene transfer (retrovirus vs. lentivirus); infused T-cell dose; intensity of conditioning chemotherapy (cyclophosphamide vs. fludarabine plus cyclophosphamide); degree of tumor burden; timing of tumor burden assessment (immediately prior to the T-cell infusion vs. at the time of enrollment); definition of CRS or neurotoxicities; and age of the treated patients. All of these variables make it challenging to compare results from one trial with those of another. Therefore, future studies from all centers conducting clinical trials in this field need to carefully examine whether the difference in efficacy and toxicity is related to CAR design, dose, conditioning chemotherapy, tumor burden at the time of therapy, or age of the patients.
CD19-targeted CAR T cells have emerged as one of the most potent therapeutic agents in ALL and serve as a strong proof of principle for this novel immune-based approach. Multicenter phase II trials are commencing shortly in both pediatric and adult ALL. Furthermore, many groups are exploring the feasibility of utilizing CAR T cells to target non-CD19 positive malignancies such as acute myeloid leukemia, multiple myeloma, brain tumors, prostate cancer, mesothelioma, and ovarian cancer, and more reports from these studies are expected in 2015.
Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5:177ra38.
Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509-1518.
Lee DW, Shah NN, Stetler-Stevenson M, et al. Anti-CD19 chimeric antigen receptor (CAR) T cells produce complete responses with acceptable toxicity but without chronic B-cell aplasia in children with relapsed or refractory acute lymphoblastic leukemia (ALL) even after allogeneic hematopoietic stem cell transplantation (HSCT) [abstract]. Blood. 2013;122:abstr 68.
Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:224ra25.
Park JH, Riviere I, Wang X, et al. CD19-targeted 19-28z CAR modified autologous T cells induce high rates of complete remission and durable responses in adult patients with relapsed, refractory B-cell ALL [abstract]. Blood. 2014;124:abstr 382.
Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study [published online ahead of print December 15, 2014]. Lancet Oncol. doi:10.1016/S1470-2045(14)71170-2.
Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507-1517.
Grupp SA, Maude SL, Shaw P, et al. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) have long term persistence and induce durable remissions in children with relapsed, refractory ALL [abstract]. Blood. 2014;124:abstr 380.
Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial [published online ahead of print October 12, 2014]. Lancet. doi:10.1016/S0140-6736(14)61403-3.
Lee DW, Stetler-Stevenson M, Sabatino M, et al. Intent-to-treat results of a phase I trial of CD19 chimeric antigen receptor engineered T cells using a consistent treatment regimen reveals a 67% complete response rate in relapsed, refractory acute lymphoblastic leukemia. Blood. 2014;124:abstr 381.
Conflict of Interests
Drs. Park and Brentjens indicated no relevant conflict of interest.
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