TAC T-Cell Therapy Shows Promise in Treating HER2+ Solid Tumors

Benjamin L. Schlechter, MD

The ongoing, phase 1/2 TACTIC‑02 trial (NCT04727151) exploring TAC01-HER2 has shown the agent to be well-tolerated with early signs of clinical activity in patients with HER2-positive solid tumors.

In both dosing cohorts of the study, TAC01-HER2 led to encouraging safety data. No dose limiting toxicities, cytokine release syndrome, or immune effector cell-associated neurotoxicity were observed, and all serious adverse events were unrelated to TAC01-HER2.

Investigators continue to examine the use of autologous T cells expressing T-cell antigen couple (TAC) that target HER2 in patients with solid tumors. According to Benjamin L. Schlechter, T-cell therapy is difficult in solid tumors. However, if successful, this study can open doors for other opportunities and advances for treatment with targeted therapies in the future.

“If we can target HER2 safely and successfully, this opens the door for a number of targets that right now are off limits…This is both an important innovation in T-cell therapy and HER2, but this is also an important innovation in cellular therapy in oncology, because products like this would allow us to target far more things than we currently can with existing technology,” Schlechter, senior physician at Dana-Farber Cancer Institute and instructor in Medicine at Harvard Medical School, told Targeted Oncology^TM in the interview.

In the interview, Schlechter discussed the potential benefit of TAC T cells for patients with solid tumors.

Targeted Oncology: Can you discuss the background and rationale for evaluating TAC T-cells?

Schlecter: Fundamentally, we know that the immune system can fight cancer and we've seen this in a myriad way with checkpoint inhibitors, chimeric antigen receptor [CAR] T therapy, TIL therapy, and other things. We also know that targets matter. The success of CAR T therapy in modern oncology is because there are unique markers in hematologic malignancies and blood cancers that are present on the cancer and on mature B cells. For example, if you eradicate all the cells with a target, you're going to be fine as a patient. You will have some transient toxicity, but it's manageable. The secret of solid tumor oncology is that our cancers are deeply similar to us. Finding a target for cellular therapy is hard. For example, if you have a target that is present on your cancer, present on your brain, and you use CAR T, an active engineered T-cell against that target, those T cells will attack that cancer and hopefully, successfully kill it and manage it, but it will also cause an on target unintended consequence, like attacking the brain. One must be careful about what they do with these engineered T cells to avoid these off-target problems or on-target, unintended problems.

We also know that 20% of all breast cancers, 20% of all gastroesophageal cancers, 5% of all colon cancers, and a few percent of lung cancers and pancreatic cancers, biliary cancers, ovarian cancers, have HER2. HER2 is a well-established marker with many treatment options. We also know that HER2 is present in your heart and lungs, so if we're going to go after HER2, which is an important cancer marker, and an important normal marker on our tissue, we need to use a T-cell product that has the ability to activate an immune response but has some discrimination between normal tissue and cancer tissue. This is an effort along that journey to figure out ways to develop T-cell products that can go after a target that's present both a normal tissue and cancerous tissue and make that distinction that a conventional CAR T can't. These cells are not a CAR T.

The T-cell receptor, the main sort of synapse between the immune cell and the cancer cell, is pretty much left native. It will behave normally, the way your T cells do right now when they surveil your HER2-positive normal tissue and don't attack it. There are other things about the cell that cause it to bind to HER2 and then help sustain an immune response. That is what leads to the difference in this product. It is not a CAR T, it's not a TIL, it's somewhere in the middle, where it's an engineered T-cell, which has the capacity to tightly bind to HER2-positive cells, but also its activation is native. Its activation of the TCR complex is based on how TCR complexes are meant to work, so it doesn't have as aggressive off-target response.

The question with these products is have we so undercut the toxicity that they were undercutting the benefit? And it looks like we're seeing early responses. We would not expect this to be as potent, early on, and low doses as a CAR T, but as engineered T cells, a TCR cell. This is an important beginning. If we can target HER2 safely and successfully, this opens the door for a number of targets that right now are off limits. There are so many things right now in oncology that we know target cancer, but we can't go after that target because there's so much targeting normal tissue that will be dangerous to do so. This is both an important innovation in T-cell therapy and HER2, but this is also an important innovation in cellular therapy in oncology, because products like this would allow us to target far more things than we currently can with existing technology.

What were the methods and design of the phase 1 study of TAC T cells in solid tumors?

This is a phase 1, dose-escalation trial with a 3 by 3 design, we're continuing escalation. We're currently in cohort 4 of the escalation. As a safety assessment as all phase 1 studies are, we're monitoring for the expected toxicity of T-cell therapy like cytokine release, drug toxicity, and monitoring for on-target and an off-target effect. So far, a small number of patients have derived benefit, pretty brisk benefit, actually, with 1 patient on day 29 with an objective response. It's still early days, we're still using low doses and escalating. We should have data on the current cohort, cohort 4, within the next few months. We have to treat those patients and wait and see what responses are, and then figure out the dosing schedule. It could be that a product like is across multiple dosing, not just dose-escalation, its dosing schedule is a first in class drug, so we're going to learn as we go, and it seems to be an appropriately safe drug. We have not seen any of the dangerous off target effects we were worried about. As I said, we have an early benefit signal, which is exciting in this product.

How does this product differ from others used in the HER2 space?

Currently, there are no cellular therapies in HER2 because of the risk of a conventional CAR T causing an on-target, unintended consequence, or inflammation of the heart or lungs. For example, there are many competing agents in the HER2 space and a big event [recently] in colorectal cancer was with the approval of tucatinib [Tukysa] with trastuzumab [Enhertu] from the MOUNTAINEER study [NCT03043313] in HER2-positive colorectal cancer. That's an important innovation. We have emerging data on trastuzumab deruxtecan, which is in HER2 in this space as well. And we have ways to treat these patients with these chemotherapeutic agents. These are agents which are critically important to have a high response rate. They have a transient response, then prolonged complete responses based on cellular immunotherapy. So far, there's nothing in the space for HER2 or really for anything outside of a small number of targets.

What are the next steps for this research?

For the TAC T product and for the TACTIC-2 study, we're going to continue dose-escalation. We need to find the recommended phase 2 dose of this product that is safe and effective, and then move quickly into a broader study for treatment in phase 2. I think that's exciting and important. If this technology works, obviously I am optimistic, this also opens the door for a myriad of targets, things that we know we want to go after, but we're afraid to do with a CAR T. It also opens the door to cellular therapy for older and less fit individuals. We have to keep in mind that solid tumors are a geriatric population in general. When we think about the patients that were offering cellular therapy to, highly toxic agents, like a CAR T with significant toxicity from lymphodepleting chemotherapy to prep for the treatment and cytokine release of neurotoxicity, and all these things, those are hard for a heavily pretreated solid tumor population and the geriatric population. We need to find technology, which is safer and equally effective or nearly as effective.

The other important consideration with technology like this is the location of care. CAR T, while there's some movement towards the outpatient, this is generally an inpatient treatment for relatively rare cancers, you can conceive of a problem, which is if we have a broadly applicable CAR T in a common cancer like colon cancer, lung cancer, breast cancer, pr prostate cancer, that requires a prolonged admission of significant toxicity. We don't have the capacity as a healthcare system to have 50,000 people a year receiving CAR T for colon cancer. We not only need to find a safe and effective treatment, we need to find treatments that we have the tools for, that we could give in the outpatient setting or with minimal hospitalization. That's why these non-CAR technologies are so important. It may be that the only pathway forward is CAR T, but I don't think so. I think that we'll be able to find somewhere below CAR to generate these immune responses safely in an older, less fit population using the resources we have.

Is there any other research that has caught your eye recently?

There's a couple of important things that we need to put into context. First of all, we had the addition of bevacizumab [Avastin] to trifluridine/tipiracil [Lonsurf] with significant, proven efficacy that was already kind of in place here in the United States based on available data. That opens up this up to a European, and international population. That that is important. I would say that boosted response rates by just over 5%. That's meaningful from 2% to 3%. There were some criticisms about that trial, that the control population in the prior lines of therapy had a little less bevacizumab in the United States, but I don't think that undercuts the benefit. I think that [trifluridine/tipiracil] with bevacizumab should represent a refractory disease standard in 1 of the standards of colorectal cancer. I think there was a good, high-quality study that was done.

Another interesting trial is the NAPOLI trial [NCT04083235] in pancreatic cancer with liposomal injection as part of a modified FOLFIRINOX regimen vs nab-paclitaxel and gemcitabine. This modified FOLFIRINOX combination was somewhat superior, but what was not really looked at was FOLFIRINOX itself. Is this better than FOLFIRINOX? Is it safer than FOLFIRINOX? And how do we contextualize the clinical realities of a somewhat more toxic regimen and how do we sequence these things, and does sequencing matter in terms of benefit? There are those who would say that gemcitabine and nab-paclitaxel no longer represent the ideal first line standard, or 1 of the 2 standards in pancreatic cancer, and it's a legitimate argument. I'm not sure it's true. I think there's still a space for gemcitabine and nab-paclitaxel. I think there are those who would say definitively that NALIRIFOX represents a new standard. I also don't think that the data is necessarily there for a couple of reasons.

First of all, we don't know if it's better than FOLFIRINOX. Second of all, it is substantially more expensive than FOLFIRINOX. The question is, what are we buying? I think that is a really well designed and important trial that answered the question of whether we do better than gemcitabine and nab-paclitaxel, but I don't think it answered the question of what's the standard first-line regimen of pancreatic cancer? I also think it's important to know that just because 1 regimen is a bit better than another regimen, that doesn't mean that we abandon the pre-existing regimen. There may be advantages with gemcitabine and nab-paclitaxel for certain individuals, and there may be advantages with NALIRIFOX for certain individuals. I don't think that this is practice changing, per se, but I think it will alter practice somewhat.

REFERENCE:
Schlechter BL, Olson D, Sailbil S, et al. A phase I/II trial investigating the safety and efficacy of autologous TAC T cells targeting HER2 in relapsed or refractory solid tumors. J Clin Oncol. 2023;41(suppl 4): TPS816. doi: 10.1200/JCO.2023.41.4_suppl