ADI-001 Highly Effective, Safe for Heavily Pretreated NHL in Preliminary Phase 1 Data

The novel, off-the-shelf CD20 CAR-modified gamma and delta T cell therapy ADI-001 demonstrated a promising early objective response rate (ORR) of 75% with a favorable safety profile for heavily pretreated patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL), according to a statement from Adicet Bio, the company developing the therapy.¹

These findings from the phase 1 study were announced separately from a presentation on the design of the study at the 2021 ASH Annual Meeting.² There were 6 patients with heavily pretreated R/R NHL enrolled at the time of the November 22, 2021, analysis, with 4 evaluable for efficacy. The ORR consisted of 2 complete responses (CR) and 1 partial response (PR) and at the time of the assessment there were no ADI-001-related serious adverse events reported, including a lack of graft-vs-host disease (GvHD), neurotoxicity, and high-grade cytokine release syndrome, which are common with other CAR T-cell therapies.

“The unequivocal responses to ADI-001 in this heavily pretreated patient population at such low dose levels are highly promising,” lead investigator Sattva Neelapu, MD, professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, said in a statement. “These data suggest that ADI-001 has the potential to be an effective treatment option for B cell malignancies if confirmed in further clinical testing. ADI-001 does not require gene editing and provides complementary innate, adaptive, and CAR-mediated antitumor effects which may improve durability and minimize emergence of tumor resistance.”

For ADI-001, cells are collected from a qualified donor and an antibody, AM3529, is used to isolate and activate the gamma delta T cells, which have HLA independent T cell receptors (TCR) and are unlikely to cause GvHD. As a result of the intrinsic benefits of these cells, ADI-001 does not require genetic engineering to remove TCRs to avoid GvHD, making them ideal for an off-the-shelf cell therapy. For ADI-001, once the gamma delta T cells are isolated, they are next transduced with a second-generation CAR specific to CD20 and store until administration. The construct has 4-1BB and CD3 zeta signaling domains.

“Gamma delta T cells have many potential advantages over conventional alpha beta T cells used for CAR T cell therapies,” Neelapu said during a presentation of the study's design at ASH. “They can impart both innate and adaptive immunity via the T cell and NK receptors on the cell surface. They have intrinsic antitumor activity that is MHC-independent, they are not expected to cause graft-vs-host disease, and they do not require T cell receptor editing.”

For the ongoing study (NCT04735471), patients are first administered a lymphodepleting regimen of fludarabine (30 mg/m² per day for 3 days) and cyclophosphamide (500 mg/m² per day for 3 days) 5 days prior to a one-time infusion of ADI-001. The protocol allows for optional pretreatment with ADI-001 following a response and safety assessment at 28 days.

The ongoing study consists of a dose escalation portion exploring 3 dose levels, starting at 30 million CAR+ cells, followed by 100 million, and finally 300 million CAR+ cells. The study plans to enroll 30 patients with R/R B cell NHL for the dose escalation portion of the study. In part 2, approximately 36 patients will be enrolled into 3 separate cohorts stratified by disease, with cohorts for diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and other subtypes of NHL. A third part of the study will explore the addition of low-dose subcutaneous IL-2 to ADI-001. This part of the study seeks to enroll 12 patients. Part 2 and 3 will utilize the maximum tolerated dose (MRD) of ADI-001 identified in part 1 of the study.

All patients enrolled in the study had at least 2 prior regimens, including treatment with an anti-CD20 antibody. ECOG performance status was either 0 or 1 and all patients are required to have adequate hematologic and organ function. Those with CD20-negative disease are excluded from the study and patients can receive a prior anti-CD19 CAR T-cell therapy but it must have been received more than 6 weeks prior to study entry.

For the early efficacy analysis announced ahead of ASH, evaluable patients had received a median of 5 prior regimens. Three of the 4 patients received the lowest dose level (30 million cells) and 1 received the second dose level (100 million cells) in part 1 of the study. At the lowest dose, there was 1 CR and 1 PR, which was a near CR. The single patient evaluable at the second dose had achieved a CR. One of the patients who experienced a CR had received a prior autologous CD19-directed CAR T-cell therapy. This patient had DLBCL.

In these 4 patients, there was a significant increase in circulating IL-15 following lymphodepletion and ADI-001 expansion and proliferation was noted by quantitative polymerase chain reaction and by flow cytometry. IL-2 and IL-8 were observed in the first 14 days following administration of ADI-001, which is an indication of ADI-001 activation. There were no meaningful IL-6 increases seen following ADI-001 treatment, except for 1 patient who developed a COVID-19 infection.

The primary end point of part 1 of the study is the incidence of dose limiting toxicities and discovery of the MTD, Neelapu noted. For part 2 and 3, the safety and efficacy of the MTD or maximum administered dose of ADI-001 will be further explored. Secondary objectives will examine pharmacokinetics, immunogenicity, and antitumor activity. The study is currently enrolling at 5 different sites in the United States.

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REFERENCES

1. Adicet Bio Announces Positive Interim Clinical Data From First-Ever Allogeneic, Off-The-Shelf, Gamma Delta CAR T Investigational Cell Therapy. News release. Adicet Bio. December 6, 2021. https://investor.adicetbio.com/news-releases/news-release-details/adicet-bio-announces-positive-interim-clinical-data-first-ever

2. Neelapu SS, Hamadani M, Stevens D, et al. A Phase 1 Safety and Efficacy Study of ADI-001 Anti-CD20 CAR-Engineered Allogeneic Gamma Delta (γδ) T Cells in Adults with B Cell Malignancies, in Monotherapy and Combination with IL-2. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2834