The first-in-human phase 1 trial of ADI-001 as a treatment for patients with relapsed/refractory B-cell non-Hodgkin lymphoma led to responses and a favorable safety profile.
According to data from a first-in-human phase 1 trial (NCT04735471) presented at the 2023 Transplantation & Cellular Therapy Meetings, treatment with ADI-001, a first-in-class, allogeneic gamma delta1 (γδ) chimeric antigen receptor (CAR) T-cell therapy, led to responses and a favorable safety profile in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.
Findings showed that patients treated at any dose of ADI-001 (n = 16) experienced an overall response rate (ORR) of 75% and a complete response (CR) rate of 69%. Additionally, 5 patients with large B-cell lymphoma (LBCL) who relapsed after prior autologous anti-CD19 CAR T-cell therapy achieved ORR and CR rates of 100%. Patients with LBCL treated at dose level 3 of 3 x 108 CAR+ cells or higher had a CR rate of 86%, and the CR rate was 75% for all patients with LBCL across all dose levels.
No dose-limiting toxicities (DLTs) or instances of graft-vs-host disease (GVHD) were reported. Additionally, no patients experienced grade 3 or higher cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity syndrome (ICANS). Thirty-eight percent of patients experienced grade 1/2 CRS, and 13% of patients had grade 1/2 ICANS.
ADI-001 is comprised of healthy donor-derived peripheral blood γδ T cells, which are genetically engineered to express a second-generation CAR targeting the B-cell–restricted CD20 antigen. After the T cells are collected through leukapheresis from a qualified healthy donor, the cells are activated and engineered by transduction of γδ T cells with an anti-CD20 retroviral vector. Following a proprietary expansion process, the final ADI-001 product is banked and available for administration to multiple patients.
“[ADI-001’s] intrinsic antitumor activity with γδ T cells is known to be MHC independent, and therefore is not expected to cause GVHD and does not require T-cell receptor gene editing,” lead study author Sattva S. Neelapu, MD, of the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center in Houston, explained in a presentation of the data.
The ongoing phase 1 trial is enrolling patients who are at least 18 years of age with relapsed/refractory B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed follicular lymphoma, primary mediastinal B-cell lymphoma, high-grade B-cell lymphoma (HBCL), follicular lymphoma, or marginal zone lymphoma.
Patients are required to have undergone at least 2 prior treatment regimens, including an anti-CD20 antibody, have documented measurable disease per Lugano 2014 criteria, have documented CD20 expression, have an ECOG performance status of 0 or 1, and have adequate hematological, renal, pulmonary, cardiac, and liver function. Toxicities from prior therapies must have resolved to either baseline or grade 1 per Common Terminology Criteria for Adverse Events v5.0. Prior anti-CD19 CAR T-cell therapy is permitted.
Key exclusion criteria include known CD20-negative B-cell lymphoma at initial diagnosis, prior cell therapy within 6 weeks, autologous stem cell transplant (SCT) within 6 weeks, allogeneic SCT or donor lymphocyte infusion within 3 months, radiotherapy within 4 weeks, treatment with immunosuppressive agents, or active autoimmune disease or infections.
Enrolled patients underwent lymphodepletion at day –5 with either cyclophosphamide at 500 mg/m2 and fludarabine at 30 mg/m2 for 3 days (standard lymphoma depletion; n = 14) or cyclophosphamide at 1000 mg/m2 and fludarabine at 30 mg/m2 for 4 days (enhanced lymphodepletion; n = 2). On day 1, patients received a single ADI-001 infusion at 3 x 107 CAR+ cells (dose level 1), 1 x 108 CAR+ cells (dose level 2), 3 x 108 CAR+ cells (dose level 3), or 1 x 109 CAR+ cells (dose level 4).
The dose-escalation portion of the trial will enroll approximately 30 total patients. Notably, a double-dose regimen of 3 x 108 CAR+ cells administered 1 week apart is being evaluated in a separate cohort.
The primary end points of part 1 of the trial are the incidence of DLTs and identifying the maximum tolerated dose (MTD). In part 2, the primary end points are to confirm the MTD or recommended phase 2 dose (RP2D) established in part 1 and to further assess safety/antitumor activity. Secondary end points include pharmacokinetics, immunogenicity, and antitumor activity, consisting of ORR, duration of response, progression-free survival, time to progression, and overall survival.
Among the 16 patients enrolled and treated prior to the December 5, 2022, data cutoff, the median age was 66 years (range, 44-75), and 63% of patients were male. Seventy-five percent of patients had LBCL, including 56% with relapsed/refractory DLBCL, 13% with HBCL (double/triple hit), and 6% with HBCL (not otherwise specified). Additionally, 19% of patients had relapsed/refractory MCL, and 6% of patients had follicular lymphoma.
The median International Prognostic Index (IPI) score for LBCL was 3 (range, 1-4), the median simplified MCL IPI score was 5 (range, 4-8), and the median follicular IPI score was 2 (range, 2-2). Seventy-five percent of patients had stage III/IV disease.
The median sum of the product of the diameters at screening was 3001 mm2 (range, 825-4006). The median prior lines of therapy was 4 (range, 2-6), and 38% of patients received prior anti-CD19 CAR T-cell therapy with either axicabtagene ciloleucel (Yescarta), lisocabtagene maraleucel (Breyanzi), or brexucabtagene autoleucel (Tecartus).
Other prior systemic anti-cancer therapy included a CD20 monoclonal antibody plus anthracycline-based chemotherapy (94%), a CD20 monoclonal antibody plus non–anthracycline-based chemotherapy (63%), chemotherapy alone (6%), polatuzumab vedotin-piiq (Polivy)/polatuzumab vedotin plus rituximab (Rituxan)/polatuzumab vedotin plus bendamustine and rituximab (31%), BTK inhibitors with or without combinations (19%), a CD20 monoclonal antibody alone (19%), lenalidomide (Revlimid) and/or tafasitamab-cxix (Monjuvi; 19%), other experimental therapies (13%), or a CD20 antibody with or without lenalidomide/bortezomib (Velcade)/venetoclax (Venclexta)/ibrutinib (Imbruvica; 6%).
At study entry, 38% of patients were refractory to first-line therapies, 69% were refractory to second-line therapies, and 69% were refractory to the last course of anti-cancer systemic therapy.
Additional data showed that patients treated at dose level 2 and dose level 3 experienced a 6-month CR rate of 33%. Patient follow-up is ongoing to assess the 6-month durability of dose level 4. The only patient to receive the double-dose regimen of ADI-001 achieved a CR, and their response was ongoing at data cutoff.
The grade 1/2 CRS rates at dose levels 1, 2, 3, and 4 were 67%, 0%, 0%, and 50%, respectively. The grade 1/2 ICANS rates were 0%, 33%, 0%, and 17%, respectively. The 1 patient treated in the double-dose cohort experienced grade 1/2 CRS but did not have ICANS.
Any-grade infection occurred in 13% of all patients, and 6% of patients had grade 3 or higher infection. Any-grade serious adverse effects (AEs) or treatment-emergent AEs occurred in 38% of patients, and 31% had grade 3 or higher serious AEs/TEAEs.
Preliminary pharmacokinetics demonstrated a robust expansion of ADI-001 measured in the peripheral blood, with peak values occurring between days 7 and 10. Persistence at dose level 4 was visible through day 28, and durability of more than 6 months was associated with ADI-001 exposure in the blood starting at dose level 2.
Neelapu also explained that γδ T cells are a preferential home to tissue, and higher levels were observed in the breast, gastrointestinal, lung, skin, bone marrow, and liver tissue/blood compared with peripheral blood. Following the presentation, John Koreth, MBBS, DPhil, of Dana-Farber Cancer Institute in Boston, Massachusetts, asked about the durability of the allogeneic cells of ADI-001.
“It’s important to remember γδ T cells are preferentially home to tissues, so we don’t know how well peripheral blood represents persistence with [ADI-001]. That is something that needs to be assessed in the future,” Neelapu said.
Enrollment for the trial is currently ongoing to provide additional data on durability and further support the RP2D.
Editor’s Note: Dr Neelapu reports patents and royalties from Takeda; consultancy for Kite, Merck, Novartis, Allogene, A Cell Medica/Kuur/Athenex, Incyte, Precision Bio, Legend Biotech, Adicet Bio, Unum Therapeutics, Bluebird Bio, Medscape, Aptitude Health, Bio Ascend, MJH Life Sciences, Sellas Life Sciences, Fosun Kite, Sana Biotechnology, Caribou, Astellas Pharma, and Morphosys; grants and research funding from Kite, Merck, BMS, Allogene, Precision Bio, Adicet Bio, Unum Therapeutics, Poseida, and Cellectis; honoraria and personal fees from Kite, Merck, BMS, Novartis, Allogene, Precision Bio, Adicet Bio, Bluebird, Medscape, Aptitude Health, Bio Ascend, MJH Life Sciences, Sellas Life Sciences, Fosun Kite, Sana Biotechnology, Caribou, Astellas Pharma, and Morphosys; and individual stocks in Longbow Immunotherapy.