Off-the-shelf CAR T-cell therapy induces durable remissions in relapsed, refractory B-cell malignancies
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ORLANDO — Off-the-shelf chimeric antigen receptor T-cell therapy induced durable remissions among patients with relapsed or refractory B-cell malignancies, according to study results presented at TCT | Transplantation & Cellular Therapy Meetings.
The lack of cytokine release syndrome and neurotoxicity suggest that a readily accessible off-the-shelf CAR T-cell product can be a viable treatment option for patients with no alternative therapy, Kevin J. Curran, MD, pediatric oncologist at Memorial Sloan Kettering Cancer Center, and colleagues concluded.
CAR T-cell therapy can benefit patients with relapsed or refractory hematologic malignancies. However, the cost, complexity of production and life-threatening toxicity often are barriers to treatment administration.
“The use of an off-the-shelf CAR-T therapy has several advantages,” Curran said. “If the cells are made in a cell bank and you have them ready, you avoid the need for bridging therapy. There is potential that the costs could be reduced if you use health donors and generate enough cells to have multiple infusions for patients. There also is the potential to have better-quality cells because you could use healthy donors as your source.”
These benefits are countered by the potential for graft-versus-host disease and the likelihood that donor cells would be rejected at some point.
Curran and colleagues transduced the 19-28z CAR into donor Epstein-Barr virus-specific cytotoxic lymphocytes (CTL) to develop an off-the-shelf CD19-specific CAR T cell.
They initiated a trial for patients with relapsed or refractory B-cell malignancies. No age restriction was used.
The initial design called for dose escalation; however, the design was modified to use a fixed dose of 3 x 106 EBV-CTL/kg for multiple infusions.
The initial design also allowed only for patients with B-cell acute lymphoblastic leukemia who underwent allogeneic hematopoietic stem cell transplant, with cells derived from the transplant donor.
Researchers expanded the trial to include patients with B-cell non-Hodgkin lymphoma or chronic lymphocytic leukemia, and to include patients who received CAR-EBV consolidation after either autologous or allogeneic HSCT. They also modified the trial to allow for use of third-party donors.
The final analysis included 10 patients (median age, 14.7 years; range, 1.3-70.5) with relapsed or refractory B-cell ALL (n = 5), NHL (n = 4) or CLL (n = 1). Seven had relapsed after allogeneic HSCT, and three received treatment as consolidation after autologous HSCT.
Eight patients were EBV-seropositive. Four patients received cells from an allogeneic HSCT donor and six received them from third-party donors. The breakdown of HLA matching between patients and donors was as follows: 10/10, n = 3; 6/10, n = 2; 5/10, n = 1; 4/10, n = 2; and 2/10, n = 2.
The median dose of T cells infused was 2.2 x 106 cells/kg (range, 0.6-7.5), median CAR T-cell dose was 0.4 x 106 cells/kg (range, 0.05-1.2) and median CAR T-cell transduction was 20.5% (range, 7.4-41).
Six patients received multiple infusions (median, 2; range, 1-3).
Dose-limiting toxicities served as the primary endpoint. Curran and colleagues also assessed optimal dose for multiple infusions, as well disease response at 1 month for patients with CLL or B-cell ALL and 3 months for those with NHL.
The therapy appeared well-tolerated.
Two patients — including one who received cells from a third-party donor — developed diffuse skin rash; one was biopsy positive for graft-versus-host disease and one was biopsy negative. These symptoms resolved after topical corticosteroids.
One patient developed grade 1 cytokine release syndrome. One patient developed reversible pneumonitis, which resolved after systemic steroids.
Researchers reported no cases of cytokine release syndrome or neurotoxicity after infusion and no dose-limiting toxicities.
Seven patients (70%) achieved response.
All four patients with NHL achieved complete response. Median follow-up was 33.9 months (range, 13-80.1) for these patients, and median OS in this group was 30.8 months (range, 8-72.9).
Five of six (83%) patients who received cells from third-party donors achieved complete response. Median follow-up for these patients was 26.9 months (range, 13-80.1), and median OS for this group was 23.6 months (range, 8-72.9).
The results suggested use of an off-the-shelf CAR product is safe and feasible for this population, and the therapy was well-tolerated, Curran said.
However, he acknowledged limitations, including the lack of standardization of conditioning chemotherapy among patients who had relapsed after allogeneic HSCT, and the fact PET/CT was not performed prior to CAR T among those who received the therapy as consolidation after autologous HSCT.
“We also had a small sample size, with only 10 patients,” Curran said. “However, we are encouraged by the results and we will continue to enroll and treat patients.” – by Mark Leiser
Reference: Curran KJ, et al. Abstract 120. Presented at: TCT | Transplantation & Cellular Therapy Meetings; Feb. 19-23, 2020; Orlando.
Disclosure: Curran reports research support from Juno Therapeutics and Novartis, as well as consultant roles with Juno Therapeutics, Mesoblast and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to TopJohn E. Levine, MD
Off-the-shelf CAR T cells that could be immediately available for use could dramatically expand access to beneficial treatment for patients with refractory or relapsed hematologic malignancies. Overcoming the risk of GVHD is essential for this approach to move into the clinic. The risk of infusing CAR T cells that also recognize host tissue and cause GVHD may be mitigated by transducing only cells that recognize EBV epitopes. In this small feasibility and safety study, the investigators showed they could create anti-CD19 CAR T cells from third-party anti-EBV CTLs. Although one patient did develop mild GVHD, the early safety signal is promising. If these results can confirmed with additional patients, this approach may find a place in the inventory of cellular therapies.
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