Allogeneic Anti-CD7 CAR-T Demonstrates Promising Results in Hematological Malignancies

Bioheng Biotech’s RD13-01, an investigational allogeneic CD7-targeted chimeric antigen receptor T-cell (CAR-T) product with genetic modifications to resist fratricide, graft versus host disease (GvHD), and rejection, demonstrated promising safety and efficacy data in a phase 1 clinical trial (NCT04538599) for patients with CD7⁺ hematological malignancies, according to results published in Cell Research.¹

Among the 11 patients evaluated for efficacy, 9 patients (81.8%) had objective responses at 28 days after treatment and 7 patients (63.6%) had complete responses (CR). Four patients remained in complete remission at a median follow-up of 10.5 months. At 28 days after treatment, 6 of the 8 patients with leukemia demonstrated either a CR or a CR with incomplete hematological recovery, and these 6 patients showed negative minimal residual disease. In terms of safety, there were no dose-limiting toxicities and no cases of GvHD or immune effector cell-associated neurotoxicity (ICANS) reported. All cases of cytokine release syndrome (CRS) were grade 2 or lower. However, several patients experienced cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) reactivation, and 1 patient death resulted from a case of EBV-associated diffuse large B-cell lymphoma (DLBCL). In addition, all treated patients experienced grade 4 neutropenia and 1 patient died of sepsis 24 days after administration of RD13-01.

"T-cell malignancies are highly aggressive hematological tumors which are generally associated with poor prognosis,” He Huang, MD, PhD, Professor of hematology, President of The First Affiliated Hospital, Zhejiang University School of Medicine, and principal investigator of the study, said in a statement.² “In particular relapsed or refractory (r/r) disease has dismal outcomes with a 5-year overall survival (OS) rate lower than 20%, there is an urgent medical need to develop novel therapies for this type of disease. Besides the marked attenuated CRS safety profile and impressive efficacy enhancement, I am also impressed with the availability and accessibility of RD13-01 for these patients with uncommon aggressive malignancies. The interval between enrollment and infusion was no more than 7 days, and no patients enrolled failed to receive RD13-01 infusion due to disease progression, leukapheresis or manufacture failure. It is expected that allogeneic CAR-T cell products provide more choices to address the unmet medical needs."

Of the 12 patients enrolled in the study who received treatment with RD13-01, there were 7 patients with T-cell acute lymphoblastic leukemia (T-ALL), 4 patients with T-cell lymphoma, and 1 patient with acute myeloid leukemia (AML).¹ The ages of the patients ranged from 8 years to 66 years (median, 34) and the patients had previously been treated with between 2 and 7 lines of therapy (median, 4). All 12 patients had at least 2 lines of prior treatment with chemotherapy, and 2 patients had previously received allogeneic hemopoietic stem cell transplant (HSCT) and 1 patient had received autologous HSCT. The 12 patients were divided into 3 dose level groups for administration of RD13-01, with 3 patients receiving 1x10⁷ cells/kg, 6 patients receiving 2x10⁷ cells/kg, and 3 patients receiving 3x10⁷ cells/kg. Dose level 2 was selected as the dose to be used in potential future studies due to all patients at this dose level achieving a response, and 5 achieving a CR.

“One patient with [peripheral T-cell lymphoma-not otherwise specified] had a CR to CAR-T cell therapy, but later developed EBV-associated B-cell lymphoproliferation (EBV-LPD) which was further progressed to DLBCL,” Huang and colleagues noted.¹ “EBV-LPD occurs frequently in patients with primary or secondary immunodeficiency disorders and can be a complication of chemotherapy, HSCT or solid organ transplantation. Our results suggest that prior EBV infection might be considered as a risk factor or exclusion criteria for CAR-T cell therapies targeting T-cell malignancies.”

Overall, Huang and colleagues concluded that the study provides support for using CD7 as a target for CAR-T therapies and for the potential of allogeneic approaches in treating patients with T-cell leukemia or lymphoma and CD7⁺ AML. The investigators additionally stated that phase 2 studies for RD13-01 are warranted to gather more information about safety and efficacy. They also identified several additional areas of interest for future research, including whether the genetic modifications on RD13-01 reduce cytokine production; whether the less intense lymphodepletion helped reduce rates of severe CRS; whether bridging to HSCT after an initial response to CAR-T therapy could assist disease control and long-term survival; a closer look at the potential risks of clonal expansion of RD13-01 and of allo-rejection by host CD8⁺CD7⁻ T-cells in allogeneic CD7-CAR-T cell therapy; and ways to prolong CAR-T cell persistence without negatively impacting expansion of CD7⁻ normal T-cells.

REFERENCES

1. Hu Y, Zhou Y, Zhang M, et al. Genetically modified CD7-targeting allogeneic CAR-T cell therapy with enhanced efficacy for relapsed/refractory CD7-positive hematological malignancies: a phase I clinical study. Cell Res. Published online September 23, 2022. Doi: doi.org/10.1038/s41422-022-00721-y

2. BiohengBiotech announces publication of impressive results with CD7-targeted allogeneic CAR-T cell therapy for relapsed or refractory T cell malignancies. News release. Nanjing Bioheng Biotech Co., Ltd. September 27, 2022. https://firstwordpharma.com/story/5656849