Kirtane Highlights Uniqueness of Solid Tumor CAR T-Cell Agent A2B530

Kedar Kirtane, MD

For patients with solid tumors, investigators have faced hurdles replicating successes with chimeric antigen receptor (CAR) T-cell therapies. The novel CAR T-cell agent A2B530, looks to forge a pathway forward in the upcoming phase 1/2 EVEREST-1 trial (NCT05736731).¹

“[Patients with] solid tumors are going to benefit from these sorts of cell therapies,” 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, said in an interview with OncLive®. “Cell therapies are the future of immunotherapies for metastatic cancers and I hope that we can come to a point where we can start curing a lot of these patients, rather than just controlling their disease for a temporary amount of time.”

EVEREST-1 will enroll approximately 160 adult patients with recurrent unresectable, locally advanced, or metastatic solid tumors that express carcinoembryonic antigen and do not express HLA-A*02. Tumor types that will make up the trial include pancreatic, colorectal, and non–small cell lung cancer.¹

To be eligible for the study, patients must have a life expectancy of at least 3 months, 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 prior allogeneic 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.¹

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 will be overall response rate. Secondary end points include persistence of A2B530 and cytokine analysis.¹

To be eligible for the EVEREST-1 trial, patients must first be appropriately enrolled in the pre-screening BASECAMP-1 study (NCT04981119). BASECAMP-1 is a non-interventional, observational study that is designed to compile information on how loss of HLA heterozygosity in a solid tumor might occur via next-generation sequencing. Patients enrolled in the trial will undergo apheresis and have their T cells stored for future use to produce A2B530 to be used as part of EVEREST-1 treatment.²

When 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. There is no time requirement between the studies, allowing patients to go directly from BASECAMP-1 to EVEREST-1 based on their own disease course.¹

Kirtane speaks on the unique mechanism of action of A2B530 and how the agent could represent a huge leap forward in the application of CAR T-cell agents for patients with solid tumors if the EVEREST-1 study proves to be positive.

What are some of the unmet needs for patients with solid tumors that led to the initiation of the EVEREST-1 trial?

We have set such a low bar for success in metastatic solid tumor cancers, that we are willing to accept minimal increases defined by a few extra months of survival for these patients. We need to have a therapy that can really extend life much longer than that, and [aim to] replicate what's happened in hematology with CAR T-cell therapies [where] people can have disease all over their body and many of those patients end up being cured.

Obviously, these are fundamentally different cancer types and within solid tumor cancers there's a variety of different malignancies, but the goal is to try to help cure many of these patients long term rather than just providing an extra couple months of survival.

I take care of head and neck cancer patients and my patients who have recurrent or metastatic disease have really 1 therapy they can receive, which works an approximate 15% to 20% of the time. So, 80% of the time, I'm going into a clinic room discussing a scan and I have to say that that cancer has progressed on that scan. There's a lot of room for improvement for many of these types of cancers.

What makes the trial design of EVEREST-1 different from other trials?

It's a unique design for a cell therapy trial. There's a master screening protocol called BASECAMP-1, where we are [enrolling] patients who have a very high risk for recurrence of their disease, whether that's colorectal, pancreatic, or lung cancer, and prescreening them for a particular blood test [result] that helps us determine eligibility for our subsequent therapeutic trial, EVEREST-1.

What is unique about this clinical trial and this cell therapy product is that it has created a unique mechanism that can distinguish tumor from normal cells. A part of that is dependent on figuring out whether a patient has that particular blood test [finding] that's relevant for EVEREST-1, and also sequencing their tumor. We're getting a lot of the prescreening out of the way, figuring out who could potentially benefit from the therapy very early on. The nice thing is that it takes advantage of a common finding in cancer, loss of heterozygosity and this is an abnormal finding for about 20% of patients with solid tumor cancers. This unique mutation allows the cell therapy product to differentiate normal from abnormal tissue.

What differentiates AB5230 from other CAR T-cell therapies?

[A2B530 uses] a novel Tmod platform that leverages loss of genes in tumors to protect normal cells and kill tumor [cells]. Basically, this CAR T has an activator and a blocker and the activator binds antigens that are uniquely expressed on tumor and the blocker binds antigens only expressed on normal cells. Basically, if one of these Tmod T cells encounters a normal cell, the blocker will block and the activator won't activate, but if it encounters a cancer cell the blocker won't be engaged, and the activator can destroy that tumor cell. It surveys both normal and abnormal cells and it can differentiate between the 2, which is the unique characteristic that will hopefully improve safety and efficacy of this cell therapy.

How does EVEREST-1 have the potential to shift the treatment landscape for patients with solid tumors?

This [trial] is really aiming for the stars because this has the potential to not only move the needle, but significantly change the paradigm through which we treat many of these patients. As I mentioned, 15% to 20% is not a good response rate, and we've accepted that as our standard for many of our solid tumor cancer patients. If this works, it has the potential to drive a completely new paradigm and a new pillar for cancer treatments.

Most of the existing [agents] have difficulty in differentiating between normal cells and tumor cells. [Although] you can have targeted therapies for tumors, it also ends up damaging normal cells, which would limit the safety and efficacy of these solid tumor cancer therapies.

Are there any safety concerns with A2B530 investigators will pay particular attention to in this trial?

The big safety concern is to ensure that that blocker really blocks because that's the [agent’s] unique way to differentiate between normal and abnormal tissue. We have to make sure that when the patients are treated on this trial, they are not experiencing major [adverse] effects. With any clinical trial, we need to make sure that it's safe and that's one of the primary end points of the trial; once it's established that it's safe then we need to make sure that it's effective for patients.

What does the future hold for this research?

This trial is focused on 1 HLA type and my hope is that if this is proven to be safe and effective, then we can expand those HLA targets long term so that they include a very diverse population of patients, because we don't want this to be only allowed for a certain patient population. Hopefully, once we have proof of concept, we can start expanding targets and expanding these HLA types as well.

References

1. 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 10, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05736731
2. 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 4, 2023. https://clinicaltrials.gov/ct2/show/NCT04981119