Baby, can you drive my CAR-T? Great potential and excitement, but questions remain
| Jun 2, 2015
Co-authored by Arnold DuBell, Ph.D., M.B.A.
In several B-cell malignancies, physicians have a number of new options for their patients, allowing these patients the promise of being treated for several lines of therapy. For chronic lymphocytic leukemia (CLL) and indolent lymphoma patients, physicians now have the option to use kinase inhibitors such as Imbruvica® (ibrutinib, Pharmacyclics/Janssen) or Zydelig® (idelalisib, Gilead). For multiple myeloma patients, physicians now have the option to utilize Kyprolis® (carfilzomib, Amgen/Onyx) or Pomalyst® (pomalidomide, Celgene). However, patients do ultimately progress even after being treated with these new agents. A Clinical Science Symposium held during the annual meeting of the American Society of Clinical Oncology (ASCO) presented early-stage data for a set of agents that give hope that this gap might be filled: chimeric antigen receptor (CAR) T-cell therapies. The fact that three abstracts on early-phase data were reviewed in a symposium dedicated to this novel mechanistic class of therapies speaks to the level of excitement this mechanism of action (MOA) is eliciting from the oncology and hematology communities.
CARs are synthetic, engineered receptors that can target cell surface antigens expressed by tumor cells. For many B-cell malignancies, a target has been most studied with this class of agents is CD19. These engineered receptors can be stably expressed on primary T-cells, allowing the engineered T-cell to dock with and kill tumor cells containing the antigen target of interest. Moreover, second and third generations of CAR-T therapies are being developed, including CD3ζ (to improve cytotoxicity), CD28 (to improve proliferation and cytokine production) and motifs such as 4-1BB or OX40 (for co-stimulatory functionality). As Dr. Ansell suggested as part of his “CAR-T 101” presentation, these “super T-cells” (not his words) will hopefully provide better responses than normal T-cells through enhanced tumor cell recognition, forced T-cell activation and increased T-cell persistence.
There were three clinical presentations during this session: two evaluating CAR-T therapies in patients with B-cell lymphomas and one evaluating a CAR-T therapy in patients with multiple myeloma. In the first presentation,1 a CAR-T therapy with only CD-28 and CD3ζ motifs (19-28z, Memorial Sloan Kettering/Juno Therapeutics) was used to treat 11 patients with relapsed/refractory aggressive B-cell non-Hodgkin’s lymphoma (NHL) after high-dose therapy and autologous stem cell transplantation (ASCT). This study was primarily designed to determine a safe dose to use for Phase II trials. The primary toxicity for this therapy was cytokine release syndrome (CRS), reported in seven patients, and this toxicity was dose-limiting in one patient. Although the post-ASCT design of this trial makes it difficult to firmly evaluate the efficacy contribution of 19-28z CAR-T, it is quite encouraging to note that four of 10 evaluable patients remain in complete remission (40%) for durations of at least 13 to 21 months.
The second presentation evaluated a different CAR-T construct in 22 heavily pretreated CD19+ lymphoma patients (13 DLBCL, 7 FL, 2 MCL).2 The construct used to generate the CAR-T therapy (CTL019; Novartis/University of Pennsylvania) contained CD-28, CD3ζ and 4-1BB motifs. The activity of the therapy was very promising in diffuse large B-cell lymphoma (DLBCL) patients: the best response rate (at three months) was 50%, with five out of six patients remaining in CR for at least six months and two responses lasting longer than a year. Of the seven evaluable follicular lymphoma patients treated with CTL019, the response rate was 100%, includingsix patients in CR at six months. To date, only two mantle cell lymphoma (MCL) patients have been enrolled, so efficacy data is very immature. Among all patients, the primary Grade 3 or higher toxicities were lymphopenia (18 patients), neutropenia (nine patients) and leucopenia (five patients). Two patients had Grade 3 or higher cytokine release syndrome (CRS), while delirium and encephalopathy occurred in one patient each.
The final abstract evaluated CTL019 in 10 patients with advanced multiple myeloma.3 This tumor type is an interesting choice for a CD19-derived CAR-T, as the majority of myeloma cells are CD19-negative. The presenter (Dr. Garfall) speculated on several rationales for this Phase I pilot study: the presence of clonotypic CD19+ B-cells or a subset of drug-resistant CD19+ cells, as well as a few cells in the dominant CD19 population with diminished copy number of cell-surface CD19 (CD19-dim). The 10 patients were already treated with ASCT and multiple lines of chemotherapy, and then treated with ASCT again along with administration of CTL019. With more than 100 days of follow-up, evidence of clinical benefit was observed in three of four evaluable patients. Moreover, two of these patients had longer and deeper responses than what they had experienced with their prior ASCT, suggesting efficacy contribution attributable to CTL019.
Although this technology is very promising, several technical hurdles remain to be solved. The two hurdles noted most often by the speakers were the persistence of the engineered T-cells and reducing the CRS and central nervous system toxicities. The last speaker (Dr. Avigen) provided current pre-clinical research – for example, addition of suicide genes within the CAR cassette to abrogate CAR-mediated toxicity, or the co-administration of select interleukins to increase persistence – that may solve some of these issues. However, the real question is whether CAR-T therapies are ready to make an impact within the next few years. In certain cases the answer appears to be a resounding “yes,” as there have been other promising data in other disease types, most notably acute lymphoblastic leukemia as well as the promising data presented at ASCO 2015 in B-cell lymphomas. However, the data presented at the ASCO Clinical Science Symposium also suggest that for other tumors types, such as multiple myeloma, the technology is not ready to let oncologists “drive your CAR-T therapy.”
1. Sauter, Abstract 8515, ASCO 2015
2. Schuster, Abstract 8516, ASCO 2015
3. Garfall, Abstract 8517, ASCO 2015