Investigators have initiated the BASECAMP-1 trial of investigational agent A2B530 with the hope of identifying patients with advanced solid tumors who will be suitable candidates for treatment in a subsequent trial.
A version of this story originally appeared on our sister site, OncLive.
To date, impressive data have been published and presented showing the effects of chimeric antigen receptor (CAR) T-cell therapies in patients with hematologic malignancies. Hoping to replicate this success in those with solid tumors, investigators have initiated the BASECAMP-1 trial (NCT04981119) with the hope of identifying individuals who may serve as suitable candidates for treatment in a subsequent trial evaluating the investigational agent A2B530 (A2 Biotherapeutics).1
Marwan G. Fakih, MD, a professor in the Department of Medical Oncology & Therapeutics Research, the codirector of the Gastrointestinal Cancer Program, and the Judy & Bernard Briskin Distinguished Director of Clinical Research at City of Hope in Duarte, California, stressed the importance of the unmet need for these treatments in solid tumors in an interview with CGTLive™'s sister publication OncLive®. “Most stage IV solid tumors are not curable. We have seen some significant advances with checkpoint inhibitors, [but] the reality is that the cure rate remains quite low. [Additionally], there are many solid tumors where we do not see any significant efficacy with checkpoint inhibitors. Therefore, there is interest in getting CAR T [therapies integrated in] solid tumors,” he said.
Advanced solid tumors, such as metastatic colorectal cancer (CRC), non–small cell lung cancer (NSCLC), and pancreatic cancer, typically coincide with poor prognoses, with 5-year overall survival rates of 14%, 6%, and 3%, respectively, and can require patients to undergo long-term treatment plans to address their needs. Additionally, the application CAR T-cell therapies to these tumors hase proven challenging thus far, in part because of a lack of tumor antigens that can distinguish cancer cells from healthy cells, with added complexity stemming from dose-limiting toxicities that have been reported in prior CAR T-cell agent studies in solid tumors.2
One such example is carcinoembryonic antigen (CEA), which has been identified as a therapeutic target of interest for the application of CAR T-cell agents in patients with solid tumors, primarily since it is expressed in most pancreatic and lung cancers, among other cancer types. Although, it is also expressed in regular epithelial cells of the gut, leading to on-target, off-tumor toxicity with several other CEA-directed therapies.3
To address these difficulties in solid tumors, A2B530 was designed using the novel, logic-gated T-cell therapy platform Tmod. These agents contain an activating receptor—either a CAR or a T-cell receptor—that recognizes an antigen on the surface of tumor cells. Specifically, it recognizes CEA and an inhibitory receptor (also known as a blocker) based on the LIR-1 protein that is designed to enhance the tumor specificity of the agent. The blocker portion of A2B530 leverages loss of heterozygosity of the antigen HLA-A*02—which is among the most common alleles seen in tumor cells in a US population—to prevent the CAR from affecting healthy tissues.2,4
“Tumors frequently have early loss of HLA—it may be an immune evasion mechanism—[and] it tends to be something that’s [present] early, therefore, you can use it to distinguish between tumor and normal cells,” J. Randolph Hecht, MD, the director of the UCLA Gastrointestinal (GI) Oncology Program and a professor of clinical medicine at the David Geffen School of Medicine at UCLA, said in an interview with OncLive. “[Approximately] 20% of major tumors, such as GI and lung, have a loss of HLA and you don’t lose it in normal cells. That’s great, but how do you leverage that?"
The first studies, Hecht explained, are being conducted using HLA-A*02 as the blocker antigen because of its commonality. "The idea is that the CAR T cell will identify the target and will not be blocked, therefore killing the cancer cells," he said. In preclinical models, A2B530 has proven effective at killing various models of tumors, and importantly, leaving the models that do not have loss of heterozygosity of HLA. "We’re starting with HLA-A*02 and CEA, [but] the whole idea is that this is a modular program. So, you can swap in [activators and blockers]. There are lots of other HLAs that might be available, plus other targets as well,” Hecht said.
BASECAMP-1 is a noninterventional screening trial enrolling patients with advanced solid tumors who could be candidates to later advance to be treated with A2B530 in the upcoming and sequential phase 1/2 EVEREST-1 study (NCT05736731). Patients with solid tumors, including CRC, NSCLC, mesothelioma, pancreatic, or ovarian cancer that are metastatic, unresectable, locally advanced, or at high risk for incurable relapse within 2 years are eligible. Enrolled individuals must also be germline HLA-A*02 heterozygous by HLA typing, have confirmed somatic loss of heterozygosity by next-generation sequencing (NGS), and have an ECOG performance status of 1 or less to be included.1
The coprimary end points are the percentage of patients who can enroll in EVEREST-1 following apheresis, and the percentage of screened participants experiencing loss of heterozygosity of HLA-A*02 as determined by NGS. The secondary end point is the rate of incidence of adverse events, which will be monitored as they relate to apheresis.
BASECAMP-1 is currently recruiting patients and is expected to be completed in December 2026. EVEREST-1 has an estimated start date of April 2023.5
The key exclusion criteria for BASECAMP include prior allogeneic stem cell or solid organ transplant, central nervous system metastases, or known infection. Patients with any other prior malignancy in the past 5 years besides non-melanoma skin carcinoma, low-grade localized prostate cancer, superficial bladder cancer, ductal carcinoma in situ of the breast, carcinoma in situ of the cervix, or stage I uterine cancer are also ineligible.
The trial will seek to identify 1000 participants to be screened for part 1 of BASECAMP-1, which will include HLA typing. Then, based on the results of the screening, approximately 500 participants will have NGS testing on their archived tumor tissue samples and be followed for up to 2 years. Blood, saliva, or buccal swabs will be obtained to determine germline HLA type and will be used for germline comparison for tumor comparison. DNA and RNA are expected to be retained for enrolled participants only, in case repeat testing is necessary.
Based on tumor NGS findings, in part 2 of BASECAMP, participants will be apheresed for peripheral blood mononuclear cell (PMBC) collection to store their T cells for EVEREST-1 upon relapse. After collection, PMBCs will be enriched for T cells and cryopreserved for future manufacturing of A2B530, with no further genetic testing performed. Archival tumor slides will be obtained for immunohistochemistry and postapheresis safety follow-up will last 7 days.
“[After apheresis], patients can resume treatment with the standard-of-care therapy that they were on, as long as it remains effective in managing their disease. The advantage of this type of design is that you are developing the product and storing it for subsequent use. The physician can decide when the best time to proceed with the CAR T-cell therapy.” Fakih explained.
“I’m very excited about both BASECAMP-1 and EVEREST-1,” Hecht added. “I am very excited about the biological model of having a blocker, because I’m afraid that otherwise it’s going to be very difficult to do cellular therapies in solid tumors. If this is the secret sauce, if this is the mechanism to overcome [the difficulties], it opens up a lot of treatment strategies for our patients who desperately need them.”