BASECAMP-1 Aims to Identify Patients Eligible for Treatment With Novel CAR T-Cell Agent

Marwan G. Fakih, MD

Looking to replicate the impressive findings with chimeric antigen receptor (CAR) T-cell therapies observed in patients with hematologic malignancies, investigators have initiated the BASECAMP-1 trial (NCT04981119) with the hope of identifying patients with advanced solid tumors who will be suitable candidates for treatment in a subsequent trial evaluating the investigational agent A2B530.¹

“It’s important to note that there are unmet needs in solid tumors; most stage IV solid tumors are not curable,” Marwan G. Fakih, MD, professor in the Department of Medical Oncology & Therapeutics Research, codirector of the Gastrointestinal Cancer Program, and the Judy & Bernard Briskin Distinguished Director of Clinical Research at City of Hope in Duarte, California, said in an interview with OncLive^®. “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.”

Patients with advanced solid tumors such as metastatic colorectal cancer (CRC), non–small cell lung cancer (NSCLC), and pancreatic cancer typically have a poor prognosis, with respective 5-year overall survival rates of 14%, 6%, and 3%, respectively, and often require long-term treatment solutions. However, applying CAR T-cell therapies to these tumors has been challenging, partially because of a lack of tumor antigens that can distinguish cancer cells from healthy cells. Additionally, dose-limiting toxicities have been reported in previous studies of CAR T-cell agents in solid tumors.²

For example, carcinoembryonic antigen (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. However, it is also expressed in regular epithelial cells of the gut, often leading to on-target, off-tumor toxicity with several other CEA-directed therapies.³

To address these hurdles in solid tumors, A2B530 was designed using the novel, logic-gated T-cell therapy platform Tmod. Tmod agents contain an activating receptor, either a CAR or a T-cell receptor, thatrecognizes an antigen on the surface of tumor cells, specifically CEA in the case of A2B530, and an inhibitory receptor, or 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 that is one of 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 theDavid Geffen School of Medicine at UCLA, said in an interview with OncLive. “[Approximately] 20% of major tumors, such as GI and lung, have loss of HLA and you don’t lose it in normal cells. That’s great, but how do you leverage that? The first studies are being are using HLA-A*02 [as the blocker antigen] because that’s the most common one found in North America. The idea is that the CAR T cell will identify the target and will not be blocked, therefore killing the cancer cells. In preclinical models, [A2B530] has been very effective at killing various models of tumors and leaving those 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.”

BASECAMP-1 Trial Design

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 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 a high-risk for incurable relapse within 2 years are eligible. Patients 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

Key exclusion criteria 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 than 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.

Approximately 1000 participants will be screened for part 1 of BASECAMP-1, which will include HLA typing. Then, based on the results of the HLA screening, approximately 500 participants will have NGS testing on their archived tumor tissue samples and be followed for up to 2 years on the study.

Additionally, 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 will be retained for enrolled participants only, in the case that repeat testing if required.

In part 2, based on tumor NGS findings, participants will be apheresed for peripheral blood mononuclear cell (PMBC) collection to store their T cells for a future interventional study upon relapse (EVEREST-1). 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. 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,” Fakih said. “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.”

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

“I’m very excited about both BASECAMP-1 and EVEREST-1,” Hecht said. “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.”

References

1. Solid tumor analysis for HLA loss of heterozygosity (LOH) and apheresis for CAR T- cell manufacturing (BASECAMP-1). ClinicalTrials.gov. Updated March 22, 2023. Accessed April 19, 2023. https://clinicaltrials.gov/ct2/show/NCT04981119
2. Simeone DM, Hecht JR, Patel SP, et al. BASECAMP-1: leveraging human leukocyte antigen (HLA) loss of heterozygosity (LOH) in solid tumors by next-generation sequencing (NGS) to identify patients with relapsed solid tumor for future logic-gated Tmod CAR T-cell therapy. J Clin Oncol. 2022;40(suppl 16):TPS2676. doi:10.1200/JCO.2022.40.16_suppl.TPS2676
3. Hecht RJ, Sandberg M, Wang X, et al. A2B530, an autologous CEA-directed Tmod T-cell therapy with an inhibitory receptor gated by HLA-A*02 to target colorectal, pancreatic, and lung cancer.
   J Immunother Cancer. 2022;10:229 doi:10.1136/jitc-2022-SITC2022.0229
4. DiAndreth B, Hamburger AE, Xu H, Kamb A. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clin Immunol. 2022;241:109030. doi:10.1016/j.clim.2022.109030
5. A study to evaluate the safety and efficacy of A2B530, a Logic-gated CAR T, in subjects with solid tumors that express CEA and have lost HLA-A*02 expression (EVEREST-1). ClinicalTrials.gov. Updated February 21, 2023. Accessed April 19, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05736731