J. Randolph Hecht, MD, discusses the challenges researchers have faced in the development of cellular therapy for patients with solid tumors, and details how A2B530 could potentially overcome some of these obstacles.
The observational BASECAMP-1 study (NCT04981119) has started screening patients to determine their eligibility for the subsequent phase 1/2 EVEREST-1 study (NCT05736731), which will investigate the novel CAR T-cell therapy A2B530 in patients with solid tumors. The cellular therapy has demonstrated promising preclinical activity with its unique mechanism of action, according to J. Randolph Hecht, MD.
“I’m very excited about BASECAMP-1 and EVEREST-1,” Hecht said. “BASECAMP-1 is a great model, and [I am] excited about the biological model of having a blocker [targeted for HLA-A*02] because I’m afraid that, otherwise, it’s going to be very difficult to [utilize] cellular therapies in solid tumors. If this is the secret sauce, if this is the mechanism to overcome [the hurdles of CAR T-cell therapy in solid tumors], it opens a lot of treatment strategies for our patients who desperately need them.”
BASECAMP-1 is enrolling patients with recurrent unresectable, locally advanced, or metastatic carcinoembryonic antigen (CEA)–expressing solid tumors which also display HLA-A*02 loss of heterozygosity—a key feature for A2B530 to be effective. As of June 2023, the first patient has been treated on EVEREST-1. EVEREST-1 is the first-in-human study of an agent based on the novel logic-gated T-cell Tmod platform that A2B530 employs, which allows it to differentiate between healthy cells and cancer cells via an activator antigen, CEA, and a blocker antigen, HLA-A*0201.
In an interview with OncLive®, Hecht, the director of the UCLA Gastrointestinal Oncology Program and a professor of Clinical Medicine at the David Geffen School of Medicine in Los Angeles, California, discussed the challenges researchers have faced in the development of cellular therapy for patients with solid tumors, and he detailed how A2B530 could potentially overcome some of these obstacles.
Hecht: We’ve been interested in cellular therapies for solid tumors for a long time. We look longingly at the results in hematologic malignancies, where patients with B-cell malignancies are getting long-term benefit.
Over the decades, we’ve looked at cellular therapy for solid tumors, and there have been a couple major problems: they don’t work very well, and they tend to have on-target, off-tumor toxicity--which is a bad combination. These may be related because in hematologic malignancies, you have a wonderful target: CD19, which is on both the malignant cell and dispensable cells.
For example, the problem with the gastrointestinal [GI] tract is that there are not a lot of dispensable organs. Once you get beyond the appendix, most of them you need. You may have a cellular therapy that is effective and has a [targetable] a tumor-associated antigen, but the problem is that there are a lot of normal cells that have the same [target].
There are several ways investigators have tried to get around this. There have been anecdotes particularlywith tumor-infiltrating lymphocytes and T-cell receptors, but there have [also] been programs shut down in solid malignancies [because of] a combination of lack of efficacy and grade 5 toxicities.
Tumors frequently have early loss of HLA [heterozygosity]—it may be an immune evasion mechanism—and therefore you can use that to distinguish between tumor and normal cells. Approximately 20% of major tumors have loss of HLA. [It is not lost]in normal cells. The whole idea is that we have something that distinguishes between tumor cell and normal cell. The [manufacturer of AB530 has] leveraged [this] is by developing a logic-gated CAR T [platform] that take advantages of a blocker they’ve developed.
The first studies are using HLA-A*02 [as the blocker] because that’s the most common one found in North America. [You would expect] normal cells to continue to have HLA. Therefore, even though they may have the target CEA, [normal cells] can be recognized by the [HLA-A*02] blocker.
The [HLA-A*02] blocker—at least in the preclinical studies—stopped the T-cell [from attacking normal cells]. The idea is that you have already pre-identified a tumor that has the target, CEA which most epithelial tumors have, and have [HLA] loss of heterozygosity. Therefore, the CAR T-cell will identify the target, will not be blocked, and will kill the cancer cell.
In preclinical models, it’s been very effective at killing various models of tumors and leaving those models that do not have [HLA] loss of heterozygosity alone. It’s something that could be leveraged. We’re starting with HLA-A*02 and CEA, but this is a modular program, so you could potentially swap in [other target and blocker antigens]. There are a lot of other HLAs that might be available, plus other targets.
Since this is a modular platform, you want to identify these patients beforehand, and then have treatments for them [later]. BASECAMP-1 is not a treatment trial. It is purely a screening and leukapheresis trial, once patients have been identified. There are a lot of trial designs where patients come in and they’re allocated to 1 arm or another depending on the characteristics of either the tumor or the patient. This is a little bit different; patients are identified early, but [treated] later.
BASECAMP-1 is scalable, so we can alter it as we go along. Right now, it is set up for patients particularly with major malignancies of non–small cell lung cancer, colorectal cancer [CRC], and pancreatic cancer who are in good shape. Good shape is important to be able to identify those patients whose normal tissue has HLA-A*02 as one of the alleles, and whose tumors have lost it, and be able to [perform] leukapheresis [on] their cells to get them and store them before they’ve had a lot of chemotherapy.
BASECAMP-1 is the first stop on your way up the mountain. If you are identified, then you can easily go on and continue to get therapy while your cells are hopefully in as good a shape as possible.
Importantly, over the last several years, the FDA has made trials like this much easier. One of the reasons is because up until relatively recently if you had an early trial you had to say patients exhausted all approved or guideline recommended options. By that time patients have gone through very minimally active therapies that have accreted over the years.
Whenever you try something new, it takes time to get the word out. First of all, only a minority of patients initially are eligible [and] there are cuts at every level. [For example,] a lot of patients are not trial eligible [for many reasons such as] they have 2 cancers or they’re 90 years old—a patient I saw this week is getting ready to go on dialysis, which has nothing to do with his cancer, [but] those are not trial candidates.
You start off with that sort of decrease [in eligibility] and only 40% of patients in North America are HLA-A*02 and that varies to a certain extent between ethnic groups; it’s a major player in all ethnic groups and it may vary a little bit where you live.
The other problem is getting the word out. It’s much easier to tell a patient, ‘I have a trial today for you,’ than ‘I’m screening you for a trial later on.’ This is not the only trial like that, and we’ve scratched our heads [trying to] figure out how to do this efficiently. I can’t say I have the best way to do it, but we’re beginning to do this, and we’re learning among ourselves what the best practices are between different institutions.
[Additionally], more patients are getting next-generation sequencing [NGS], and I feel that all patients who have metastatic disease deserve NGS. Often a patient may have their tumor initially looked at before they’re metastatic, but especially in CRC, as well as pancreatic and lung cancer, you learn so much about the usual suspects, like RAS in lung cancer or BRCA in pancreatic cancer. There are lots of other things that can be obtained from [NGS]. As NGS gets better, they will be able to [better] identify HLA types.
BASECAMP-1 is very safe. We have blood that’s being drawn, we can do buccal swabs that have very low risk, [and] leukapheresis has very minimal risk. The risk for the patient is truly minimal.
EVEREST-1 is a first-in-human [study] with this CAR T-cell [therapy], and even though the design mitigates toxicity and maintains efficacy, [we still must monitor for toxicity]. No efficacy doesn’t do your patients any favors because they still need lymphodepletion, they get chemotherapy, and they’re being taken away from other potential modestly active therapies. That’s an open question [because] we know that CAR T-cell therapies and other cellular therapies can have serious toxicity, and we’re hoping that we’ll be able to overcome this.
A2 Bio announces first patient dosed in phase 1 clinical trial of A2B530, a novel cell therapy for the treatment of colorectal, pancreatic, and non-small cell lung cancers. News release. A2 Biotherapeutics, Inc. May 30, 2023. Accessed September 13, 2023. https://www.a2bio.com/a2-bio-announces-first-patient-dosed-in-phase-1-clinical-trial-of-a2b530-a-novel-cell-therapy-for-the-treatment-of-colorectal-pancreatic-and-non-small-cell-lung-cancers/