September 2015, Vol. 2, No. 5
CAR-T Cells Moving Along in Hematologic Malignancies
There is excitement about immunotherapy for the treatment of several types of tumors, and the list of cancers amenable to this approach is expanding. In addition to the programmed death-1 (PD-1) and its ligand 1 (PD-L1) immunotherapies, chimeric antigen receptor T (CAR-T)-cell therapy is also garnering much interest, especially in patients with hematologic malignancies who have exhausted other treatment options, but it is still early days for CAR-T therapy.
CAR-T cells utilize the patientâs own T cells, which have been genetically engineered ex vivo to target surface antigens expressed on the surface of tumor cells, most often CD19; the CAR-T cells are then reinfused into the patient, where they attach to the receptor and kill the tumor cells that contain the antigen target. Second- and third-generation CAR-T cells are under development, targeting different domains (such as CD38, CD3z, 4-IBB) with the goal of improving cytotoxicity and functionality.
A clinical science symposium at ASCO included 3 presentations on CAR-T cells being studied in hematologic malignancies. Two of these evaluated CAR-Tâcell therapies in patients with B-cell lymphomas and one in patients with multiple myeloma.
B-Cell Non-Hodgkin Lymphoma
A phase 1 clinical trial enrolled 11 patients with poor-risk relapsed/refractory, aggressive B-cell non-Hodgkin lymphoma (NHL) following high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) to receive treatment with 19-28z CAR-T cells. The study was designed to identify a safe dose of CAR-T (Abstract 8515).
The median age of patients was 61 years (range, 34-75 years), and the median number of prior lines of therapy was 2 (range, 2-4). Seven of 11 patients developed grade â¥3 cytokine release syndrome (CRS) with primarily central nervous system toxicity, an adverse event known to occur with CAR-T therapy. Treatment with tocilizumab, an interleukin-6 inhibitor, reversed CRS.
At the time of ASCO, 4 of 10 evaluable patients remained progression-free 13 to 21 months after HDT-ASCT.
âThere has been little progress in 20 years in treating relapsed/refractory lymphoma proceeding to transplant. This is the first study of 19-28z CAR-T cells following consolidative HDT-ASCT for poor-risk relapsed/refractory NHL, and 19-28z CAR-T cells appear to be a promising approach in this population,â said lead author Craig Sauter, MD, Memorial Sloan Kettering Cancer Center, New York City.
CD19-Positive B-Cell Lymphomas
A phase 2 trial evaluated a different CAR-T construct in 29 heavily pretreated patients with CD19-positive lymphoma (19 diffuse large B-cell lymphoma [DLBCL], 8 follicular lymphoma [FL], 2 mantle cell lymphoma [MCL]) (Abstract 8516). These CAR-T cells were engineered to contain CD28, CD3z, and CD137 (4-1BB) motifs.
These patients had no other available treatment options and were expected to survive for at least 12 weeks.
In the DLBCL group, overall response at 3 months was 2 complete responses [CRs] and 4 partial responses [PRs]. Six patients had progressive disease (PD), and 1 was not evaluable. Three patients with PR at 3 months converted to CR by 6 months; 1 patient with PR at 3 months had PD at 6 months. Median progression-free survival (PFS) was 90 days. Median duration of response was not yet reached at a median follow-up of 274 days.
In the FL group (8 patients), response was 100% in the 7 evaluable patients (3 CRs, 4 PRs). Response at 3 months was 100% (6 CRs, 1 PR). Three patients with PR at 3 months converted to CR by 6 months. One patient with PR at 3 months remained in PR at 6 and 9 months but developed PD at approximately 12 months. Median PFS was not yet reached.
Efficacy data were too immature to report for the 2 patients with MCL.
âCTL019 achieved durable response in patients with relapsed/refractory CD19+ DLBCL and FL. All patients who achieved CR remain in CR. The toxicity of this approach appears acceptable. Cytokine release syndrome was generally grade 2, and no deaths were reported fromÂ CRS,â stated lead author Stephen J. Schuster, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
The final abstract evaluated CTL019 in 10 patients with advanced multiple myeloma. Multiple myeloma would not be an intuitive choice for CD19-derived T cells, as the majority of myeloma cells are CD19 negative (Abstract 8517).
âWe hypothesized that CTL019 would exhibit efficacy in multiple myeloma due to low-level CD19 expression on myeloma plasma cells or CD19 expression in drug-resistant, disease-propagating subsets of the myeloma clone,â explained lead author Alfred L. Garfall, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
All 10 patients had received ASCT followed by multiple lines of chemotherapy; then they were treated again with ASCT plus CTL019. At more than 100 days of follow-up, clinical benefit was seen in 3 of 4 evaluable patients. Two of the 3 patients had deeper and longer responses than they had on prior ASCT, suggesting that CTL019 contributed to improved efficacy.
Speakers agreed that the technology appears to be able to make an impact in acute lymphoblastic leukemia, according to published studies and studies presented at other meetings, and in studies in B-cell lymphomas presented at ASCO. The answers are not in yet for multiple myeloma and other tumor types.
Researchers are still working on how to reduce or abrogate CAR-Tâmediated toxicity, such as CRS and central nervous system toxicity, and how to improve the persistence of the engineered T cells once they are reinfused into the patient.
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