Harnessing a Unique Approach With A2B530 to Bring CAR T Treatment to Solid Tumors
The BASECAMP-1 clinical trial will aim to find patients with advanced solid tumors who are good candidates for the subsequent EVEREST trial.
A version of this story originally appeared on our sister site, OncLive.
Diane M. Simeone, MD
The BASECAMP-1 clinical trial (NCT04981119) is now underway, initiated by investigators with an aim to identify patients with advanced solid tumors who would qualify for another trial, the phase 1/2 EVEREST trial (NCT05736731), which is evaluating the investigational chimeric antigen receptor (CAR) T-cell therapy A2B530.1,2
Currently, there are no FDA-approved CAR T-cell agents available for patients with solid tumor malignancies. Several phase 1 clinical trials are in progress to assess the safety and efficacy of these therapies—as monotherapy and as part of combination regimens—in solid tumor malignancies, including glioblastoma, as well as gastrointestinal, renal, prostate, ovarian, and thoracic cancers.2 Despite these ongoing efforts, though, there have been challenges with bringing CAR-T treatments to the solid tumor landscape.
One obstacle this development among patients with solid tumors, aside from the sheer complexity of the tumor microenvironment, is the lack of specificity to affect the relevant target antigens. With some agents, fatal adverse effects (AEs) have been reported, with instances of damage to healthy tissues that also expressed the target antigen. As well, tumor antigens in solid tumors tend to be more heterogeneous compared with those in hematologic malignancies, which has created circumstances of inconsistent and incomplete malignant cell death.2
Challenges in Solid Tumors
Take carcinoembryonic antigen (CEA) for example. CEA has been identified as a therapeutic target of interest for the application of CAR T-cell agents in patients with solid tumors because it is expressed in most pancreatic and lung cancers, among other cancer types. Although, CEA is also expressed in regular epithelial cells of the gut, and this has led to on-target, off-tumor toxicity with several other CEA-targeted treatments.3
“There have been unique challenges in [applying CAR T-cell therapies to] solid tumors, [including] understanding of the tumor microenvironment,” Diane M. Simeone, MD, the director of the Pancreatic Cancer Center and the associate director of translational research at the Perlmutter Cancer Center in New York, told CGTLive™'s sister publication, OncLive®. “However, with increasing analysis of human tumors, in particular with the burgeoning field of single-cell sequencing, we’re getting a much more detailed look into the tumor microenvironment of solid tumors."
"That is going to help us drive new technologies in immunotherapy. With CAR T, there are advances in the technological aspects of T-cell preparation, targeting strategies, and strategies to mitigate off-target effects. The combination of these things coming together is hopefully poising us to move CAR T-cell therapy into effectiveness for solid tumors," Simeone continued.
To address these hurdles in solid tumors, A2B530 was designed using the novel, logic-gated T-cell therapy platform Tmod. Agents developed via Tmod contain an activating receptor, either a CAR or a T-cell receptor, that recognizes an antigen on the surface of tumor cells—in the case of A2B530, CEA—and an inhibitory receptor (also known as a blocker) based on the LIR-1 protein designed to enhance the tumor specificity of the agent. The blocker portion of A2B530 leverages loss of heterozygosity of the antigen HLA-A*02, one of the most common alleles in US populations of tumor cells, to prevent the CAR from affecting healthy tissues.3,5
Existing literature has suggested that the LIR-1 “blocker” might be able to recognize molecules with HLA-I family-shared properties. Furthermore, this blocking mechanism is self-activated and specifically mitigates cross-reactivity when active. This blocking effect results in high specificity for Tmod agents when it comes to killing tumor cells compared with normal cells, and Tmod cell activation has shown reversibility.5
“This novel Tmod platform leverages loss of genes in tumors to protect normal cells while killing tumor cells,” Kedar Kirtane, MD, the physician director for engagement of special populations for clinical trials and an assistant member in the Department of Head and Neck-Endocrine Oncology at Moffitt Cancer Center in Tampa, Florida, told OncLive. “This CAR T has an activator and a blocker; the activator binds antigens that are uniquely expressed on tumor and then the blocker binds antigens only expressed on normal cells. If one of these Tmod T cells encounters a normal cell, the blocker will block and the activator won’t activate."
A2B530 is classified as a Tmod CAR T-cell therapy that targets tumors that express CEA and are also without HLA-A*02.5 Kirtane continued on that front, noting that if the T cells come across a cancer cell, "the blocker won’t be engaged, and the activator can destroy that tumor cell. So it surveys both normal and abnormal cells and it can differentiate between the 2, which is really the unique characteristic that will hopefully improve safety and efficacy of the cell therapies.”
Preclinical findings evaluating the efficacy A2B530 in targeting colorectal, pancreatic, and lung cancer cells were presented at the Society for Immunotherapy of Cancer’s 37th Annual Meeting in Boston, Massachusetts, in November 2022. T cells from HLA-A*02–positive donors were transducedwith a single lentivirus to express the CAR, the blocker, and an shRNA-targeting β2M. NOD scid gamma mice subcutaneously implanted with normal (CEA-positive, HLA-A*02-postive) and tumor (CEA-positive, HLA-A*02-negative) cells were used to examine the in vivo activity of A2B530. The mice were subsequently treated with A2B530 or control T cells intravenously.3
Data from the preclinical study showed that the control CEA CAR T cells killed CEA-positive target cell lines regardless of HLA-A*02 expression and the CEA Tmod cells selectively killed tumor cells. Notably, in mixed cell cultures, CEA Tmod cells killed only the HLA-A*02-negative target cells and the control CAR killed both the HLA-A*02-negative and HLA-A*02-postive cell lines. The Tmod cells also displayed bidirectional control between the activated and blocked states.3
EVEREST-1: A2B530 in Solid Tumors
Eligibility for the EVEREST-1 trial includes patients who are appropriately enrolled in the BASECAMP-1 study, which is a noninterventional, observational study designed to compile information—via next-generation sequencing—on how a solid tumor might lose HLA. Patients enrolled in the trial will undergo apheresis and have their T cells stored for future use to produce A2B530 as part of EVEREST-1.5
Once disease progression occurs, eligible patients in BASECAMP-1 will be screened for EVEREST-1 and the patient’s T cells will be used to manufacture A2B530. The studies have no time requirement between them, allowing patients to go directly from BASECAMP-1 to EVEREST-1 based on their own disease course.1,2
“It’s a very unique design for a cell therapy trial. We’re getting a lot of the prescreening out of the way and figuring out who could potentially benefit from the therapy very early on,” Kirtane said. EVEREST-1 is seeking to enroll approximately 160 adults with recurrent unresectable, locally advanced, or metastatic solid tumors that express CEA and do not express HLA-A*02. Tumor types that will be included in the trial are pancreatic, colorectal, and NSCLC.2
Additionally, those in the trial must have a life expectancy of at least 3 months, have an ECOG performance status of 1 or less, have received previous therapy for their solid tumor, and have adequate organ function. Those who have undergone priorallogeneic stem cell or solid organ transplant, a cancer therapy within 3 weeks or 3 half-lives of A2B530 infusion, or radiotherapy within 28 days of A2B530 infusion will not be included.2
The coprimary end points of the phase 1 portion of the study are the rate of adverse events and dose-limiting toxicities as well as determining the recommended phase 2 dose. In phase 2, the primary end point is overall response rate. Secondary end points include persistence of A2B530 and cytokine analysis. The trial is not yet recruiting patients, with ancipated completion slated for December 2028.2
“With this trial and some others that are coming on board, we’re in a unique position to really evaluate for the first time pretty compelling approaches in testing CAR T-cell therapy in solid tumors. I’m very excited for the opportunity to offer this therapy for our patients. I am looking forward to seeing how this approach can be best deployed and to broaden the portfolio of patients that will be eligible for this treatment by increasing the activator portfolio along with the HLA subtypes that are eligible for the trial,” Simeone said.
