Identifying Patients for EVEREST-1 Trial of CAR T-Cell Therapy in Solid Tumors
Marwan G. Fakih, MD, discusses how the BASECAMP-1 and EVEREST-1 trials will work in concert, diving into the unique mechanism of action of A2B530.
A version of this story originally appeared on our sister site, OncLive.
Marwan G. Fakih, MD
The use of extensive screening tools for patients with solid tumors expressing human leukocyte antigen (HLA) loss of heterozygosity should allow for investigators in the observational BASECAMP-1 study (NCT04981119) to determine which patients will derive the most benefit from treatment with a novel chimeric antigen receptor (CAR) T-cell therapy, A2B530, in the simultaneous phase 1/2 EVEREST-1 study (NCT05736731).
One of those investigators is Marwan G. Fakih, MD, the Judy & Bernard Briskin distinguished director of Clinical Research, associate director for Clinical Research, codirector of the Gastrointestinal Cancer Program, and medical director of the Judy & Bernard Briskin Center for Clinical Research at City of Hope in Duarte, California. Fakih expressed his excitment in the trial, calling the science it sets up "phenomenal," and noting that sparing the normal cells from the potential toxicity of the CAR T treatment that has been shown in vitro is "amazing."
Despite that many patients are receptive to the prescreening process, the challenge faced by the investigators is the percentage of them who are eligible for apheresis. "You have to go through a lot of screening to identify the right individual, but the potential of this technology is significant and certainly makes it worth it to proceed with this wide screening process to identify the right patient,” Fakih said.
As of June 2023, EVEREST-1 has dosed the first patient with A2B530, and BASECAMP-1 is currently enrolling patients with recurrent unresectable, locally advanced, or metastatic carcinoembryonic antigen (CEA)-expressing solid tumors with HLA-A*02 loss of heterozygosity.1 The selectivity of the novel logic-gated T-cell Tmod platform that A2B530 is based on allows the CAR T-cell agent to differentiate between healthy cells and cancer cells via an activator antigen, CEA, and a blocker antigen, HLA-A*0201.
BASECAMP-1 will screen patients for HLA-A*02 loss of heterozygosity and perform apheresis on eligible patients to collect and store their T cells to produce A2B530 for subsequent treatment if the patient is enrolled to EVEREST-1. In an interview with CGTLive™'s sister publication, OncLive®, Fakih discussed how the trials will work in concert and dove deeper into the unique mechanism of action of A2B530.
What have been some barriers to providing effective CAR T-cell therapies in solid tumors?
Marwan G. Fakih, MD: It’s important to note that there are unmet needs in solid tumors and most stage IV solid tumors are not curable. Although we have seen some significant advances with checkpoint inhibitors, the reality is that the cure rate with checkpoint inhibitors remains quite low. There are many solid tumors where we do not see any significant efficacy for immunotherapy with checkpoint inhibitors. Therefore, there is interest in getting CAR T-cell therapy in solid tumors.
However, the challenges have been that, in contrast with some hematological malignancies, solid tumors don’t typically have a high expression of tumor-specific antigens that are not expressed on normal tissue. When you look at tumor markers that are expressed in cancer cells, those tumor markers are not necessarily expressed in normal cells. For example, CEA is a very common antigen that we target, and the challenges have been that CEA is also expressed in normal tissue; therefore, prior CAR T-cell technologies looking at targeting such tumor antigens have been associated with significant toxicities and these toxicities have been an obstacle for developing CAR T [therapies].
There have been some novel ways of going around that, one of which has been to focus on targeting somatic alterations in tumors and there is work that is being done in that regard. Also, as exciting [is] the development of [this] Tmod platform, where you can target an antigen that is expressed in normal cells but find a way to prevent that same CAR T-cell therapy from attacking the normal cell in the event that the normal cell expresses the same antigen [as the cancer cell].
How does the novel Tmod platform allow A2B530 to distinguish between normal and cancer cells?
One of the ways of addressing the ubiquitous [nature] of these tumor antigens and their presence in normal cells is to try to figure out a way to inhibit CAR T [cells] from attacking normal cells. This specific Tmod platform, the CAR T-cells will have both a blocker and an activator. The blocker receptor binds to an HLA antigen on normal cells and the activator receptor binds to the neoantigen, and specifically here in this platform, CEA is the first [antigen] to be tested as an activator.
To be able to inhibit the CAR T [product from affecting] normal cells, that blocker antigen should be expressed only in normal cells and cannot be expressed in tumor tissue. Therefore, the focus of this platform is on loss of heterozygosity. Basically, you’re trying to select patients with tumors that have lost the expression of HLA that is the specific antigen blocker for the CAR T-[cell therapy]. The initial development will focus on HLA-A*0201 because that’s the most prevalent HLA in patients. Therefore, the Tmod is looking at an activator antigen, which is CEA, and a blocker antigen, which is HLA-A*0201.
The study will select HLA-A*0201-positive patients, but to treat them their tumor should have lost the [heterozygosity of] HLA-A*0201. Therefore, the tumor itself loses the ability to activate the blocker receptor and [also] has the activator antigen that activates the activator receptor on the CAR T-cell.
How does the study design of BASECAMP-1 work in conjunction with EVEREST-1?
BASECAMP-1 is a screening and apheresis trial to identify the patients who could be candidates down the road for treatment [in EVEREST-1] with the Tmod CAR T-cell [therapy] that is targeting CEA. We're focusing on identifying patients with HLA-A*0201, so the first step in the screening process is to perform HLA typing on these patients, [then] identify those who are HLA-A*0201-positive. We expect approximately 30% of the population to be HLA-A*0201-[positive]. Those individuals who are harboring an HLA-A*0201 phenotype and have specific malignancies that are expected to be CEA-producing, such as colon cancer, pancreatic cancer, and non-small cell lung cancer, will have their tumors tested for loss of heterozygosity of HLA-A*0201.
The expectation is that somewhere around 15% to 20% of patients will have loss of heterozygosity. So approximately 15% to 20% of the 30% of patients who have HLA-A*0201 will be candidates for apheresis—that’s expected to be somewhere between 5% to 10% of the overall population with these specific tumors. At that point, those patients who are identified to be HLA-A*0201-positive and at the same time are identified to have loss of heterozygosity will be offered apheresis, so that the CAR T cells can be developed for treatment [in EVEREST-1].
After apheresis, these 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 [A2B530], storing it for subsequent use, and then the physician can decide when the best time is to proceed with CAR T-cell therapy.
What qualifies a patient to advance from BASECAMP-1 to EVEREST-1?
The first step is [for the patient to be treated with ]an apheresis product. After that, the patient should still satisfy certain criteria. No. 1, you don’t want to enroll a patient who is responding to current therapy and move them to a CAR T treatment at that point; you have to have some assessment that proves this patient is no longer benefiting from the standard therapy that they are receiving.
There are also multiple other criteria that are related to organ function [and] fitness of the patient. In general, you need to know that the patient will be able to tolerate conditioning therapy and CAR T treatment, as well as have a reasonable chance of cruising through the therapy without major toxicity. [Suitable] liver function tests, performance status, renal function, having no other contraindications to treatment or conditioning, etc. In general, [these trials have] typical CAR T-cell therapy inclusion/exclusion criteria.
Are there any safety concerns clinicians should be aware of in the BASECAMP-1 trial?
Not for the BASECAMP-1 portion…because it’s an apheresis study identifying the patients and then harvesting the white [blood] cells for future treatment. There are no concerns there [because] you can stop chemotherapy for a couple of weeks prior to apheresis, and after that, the patient can resume treatment. The concern maybe would be that there is a very short interruption of treatment, but this is not a protracted interruption of therapy.
