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Point-of-care bispecific targeting ‘offers new paradigm’ for CAR T-cell therapy
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CHICAGO — A novel bispecific anti-CD19 and anti-CD20 chimeric antigen receptor T-cell therapy has shown promising overall response rates for the treatment of relapsed or refractory non-Hodgkin lymphoma, according to phase 1 trial results presented at ASCO Annual Meeting.
Patients treated during this dose-escalation and expansion trial demonstrated an 82% ORR at day 28 after infusion with a bispecific lentiviral CAR T cell (LV20.19CAR) that targets both CD20 and CD19 B-cell antigens.
“While CD19 CAR-T cell therapies are effective, most patients with non-Hodgkin lymphoma still fail treatment either due to a lack of response or relapse after initial response,” Nirav N. Shah, MD, MSHP, assistant professor of medicine in the division of hematology and oncology at the Medical College of Wisconsin and the trial’s principal investigator, told HemOnc Today. “Through dual targeting of both CD19 and CD20 receptors characteristic for B-cell [non-Hodgkin lymphoma], utilizing a bispecific CAR, we were hopeful to improve clinical outcomes for patients with relapsed or refractory [non-Hodgkin lymphoma] and limit antigen escape.”
The trial used a starting dose of 2.5 x 105 cells/kg (with a target dose of 2.5 x 106 cells/kg) to evaluate safety based on the incidence of dose-limiting toxicities in the 28 days after infusion of LV20.19CAR. All patients underwent lymphodepletion with fludarabine plus cyclophosphamide before receiving LV20.19 CAR T cells.
“To our knowledge, this is the only bispecific, tandem CAR T against CD19 and CD20 currently under clinical investigation in the United States,” added Shah, a HemOnc Today Next Gen Innovator.
“Additionally, we are using a novel production system, the CliniMACS Prodigy (Miltenyi Biotec), to produce CAR T-cell therapy in an efficient, point-of-care fashion without third-party shipping of cells,” he added. “Point-of-care CAR T and bispecific targeting offers a new paradigm for the administration of CAR T cells and the treatment of patients with relapsed or refractory [non-Hodgkin lymphoma].”
Shah noted that this point-of-care CAR T-cell production allowed patients in the study to receive multiple split infusions rather than a single infusion, in addition to the infusion of fresh modified cells instead of frozen cells.
Seventeen patients (median age 59 years; range 41-71) have been treated with LV20.19CAR, including 8 patients with DLBCL, six with mantle cell lymphoma, two with chronic lymphocytic leukemia, and one with follicular lymphoma. Nine patients participated in the dose-escalation phase of the trial and eight participated in the dose-expansion phase (6 split infusion, 2 single infusion). Three patients each were treated at 2.5 x 105 cells/kg, 7.5 x 105 cells/kg, and 2.5 x 106 cells/kg during the dose-escalation phase; no patient experienced dose-limiting toxicity. A dose of 2.5 x 106 cells/kg was selected for the expansion phase of the trial.
At day 28 after infusion, researchers observed an ORR of 82% (14 of 17 patients), including 11 complete responses and three partial responses. All patients who had a complete response remain in remission to date, with the longest exceeding 1.5 years. Eleven patients were treated at the goal dose level of 2.5 x 106 cells/kg, with 9 patients achieving a complete response.
Shah said the results of the phase 1 study “demonstrated exciting clinical responses” that should be confirmed with larger phase 2 clinical trials. He also noted that antigen downregulation was not identified as a mechanism of resistance among patients who did not respond to treatment with LV20.19CAR.
Eleven patients experienced grade 1 or grade 2 cytokine release syndrome, whereas five patients experienced neurotoxicity, of which two had grade 3 neurotoxicity. There were no cases of grade 3 or grade 4 cytokine release syndrome or grade 4 neurotoxicity. Tocilizumab (Actemra; Genentech) was given to five patients to treat symptoms of cytokine release syndrome.
“While we were concerned that dual targeting of two B-cell receptors may exacerbate CAR T-cell toxicity, we were surprisingly pleased with the toxicity profile,” Shah told HemOnc Today, highlighting that no patient in the trial required ICU-level care after infusion of LV20.19CAR.
“We hope that this form of CAR T-cell therapy is more effective and potentially safer than the current products in place, although larger studies are needed to confirm the early findings in this small phase 1 study,” Shah said. “Furthermore, we feel that point-of-care CAR T production allows flexibility in patient care, as we highlighted in our study.” – by Drew Amorosi
Reference:
Shah NN, et al. Abstract 2510. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Shah reports stock and other ownership interests in Cidara Therapeutics, Exelixis, Geron and Oncosec; consultant/advisory roles with Incyte, Jazz Pharmaceuticals, Juno Therapeutics and Kite Pharma; research funding from Miltenyi Biotec; and travel, accommodations and expenses paid by Miltenyi Biotec. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Brian T. Hill, MD, PhD
There are two novel and interesting aspects to this phase 1 study of bispecific anti-CD19, anti-CD20 CAR T cells for relapsed, refractory, non-Hodgkin lymphoma. First is the use of “point-of-care” manufacturing of CAR T cells, as opposed to CAR T cells currently in use, which are centrally manufactured. The process used in this study helps remove some logistical barriers that are present in the currently employed CAR T-cell therapy process through commercial use. It will be interesting to see if this model becomes a viable approach either for standard treatment or through an increasing number of phase 1 trials.
The second novel aspect of this approach is that the CAR used in this study targets not just CD19, but CD20 as well, making it a bispecific CAR. To my knowledge, this is the first clinical trial data in lymphoma using a bispecific CAR.
There was a very significant ORR of 82% for heavily pretreated patients with non-Hodgkin lymphoma which, for a phase 1 study, is remarkable, particularly as many of the patients received one of the lower cell dose levels. The complete response rate of 54% also was very respectable compared with current commercially available CAR T-cell products.
We know that one of the major mechanisms of resistance to CD19 CAR T-cell therapy is antigen loss, which is well-described in previous studies to occur in patients with acute lymphoblastic leukemia and B-cell lymphomas. The results of this trial show a very important path forward using a bispecific CAR with two targets to potentially mitigate the possibility of antigen loss.
From a safety and tolerability standpoint, the bispecific CAR being tested in this trial is on par with, or possibly even safer than, existing CAR T-cell products with the caveat that not all patients received the highest cell dose level. There were cases of cytokine release syndrome, which is likely inherent to the treatment process, but neurotoxicity in this trial was mild.
At least one of the patients in this trial had undergone previous commercial CD19 CAR T-cell therapy and went on to have a complete response to the bispecific CAR being tested. Because at least half of the patients with aggressive B-cell lymphomas treated with commercial anti-CD19 CAR T-cell therapy will not achieve durable remissions, there are very limited options for these patients. Bispecific CAR T-cell therapy as described in this study may be the next step on the way to improving these patients’ outcomes.
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