HER2-Directed CAR T-Cell Therapy Appears Active in Phase I Trial for Advanced Sarcoma

Shoba A. Navai, MD

Shoba A. Navai, MD

Patients with sarcomas, including osteosarcoma in particular, have limited treatment options available, and the landscape has not advanced in over 40 years, according to Shoba A. Navai, MD. However, trials are now evaluating the potential role of chimeric antigen receptor (CAR) T cells as treatment of patients with sarcoma.

In a phase I clinical trial, HER2-directed CAR T-cell therapy and lymphodepleting chemotherapy demonstrated encouraging early findings in both pediatric and adult patients with advanced HER2-positive sarcoma.These data were presentedlast year during the 2019 American Association for Cancer Research (AACR) Annual Meeting.

HER2 expression has been observed in a number of different cancer types, but levels of expression are lower in sarcoma compared with disease types such as breast cancer where the HER2 gene is amplified. However, CAR T cells can detect HER2 expression at much lower levels.

While CAR T-cell therapy has been most successful in hematologic malignancies, Navai advocates for more research in the solid tumor space. Based on the early findings from the phase I study (NCT00902044), this treatment appears promising for the treatment of patients with sarcomas and other solid tumors.

In an interview withTargeted Oncology, Navai, an assistant professor in the Department of Pediatrics, Section of Pediatric Hematology and Oncology at Baylor College of Medicine, discussed the evolving role of CAR T-cell therapy in solid tumors, including sarcomas and how the efficacy and safety compare with CAR T cells in this space compared with hematologic malignancies.

TARGETED ONCOLOGY:  What does the current treatment landscape look like for patients with relapsed/refractory sarcoma?

Navai:Patients with relapsed or refractory sarcomas have very limited treatment options. For example, in osteosarcoma over the last 40 years, despite all the trials that have been done, there has been no improvement in overall survival. Patients do have chemotherapy options, and there new targeted agents are coming out. However, none of them have shown great efficacy so far.

TARGETED ONCOLOGY: What is the role of HER2 expression in sarcoma?

Navai:HER2 is expressed in a variety of cancers, including some sarcomas, but unlike breast cancer, it is not gene amplified. The levels of surface expression are much lower, and HER2 antibodies have not worked. T cell therapies have the ability to detect HER2 even at much lower levels.

TARGETED ONCOLOGY: How has the role of CAR T-cell therapy evolved in the treatment paradigm for other cancer types compared to sarcomas?

Navai:CAR T-cell therapies for cancer have been most successful in the arena of hematologic malignancies, specifically the CD19 CAR T cells. In the solid tumor field, unfortunately, we have not had as much success just yet, but there are many researchers working on this field. Solid tumors present some challenges that hematologic malignancies do not have. Specifically, the solid tumor microenvironment and the immune inhibitory cells are not necessarily present in hematologic malignancies. There is also a lack of targets, which is the biggest challenge.

TARGETED ONCOLOGY: Can you expand on how this approach may be more effective than what is currently being used?

Navai:Our study was a phase I study, so the primary purpose was to determine the safety of administering these cells. We were fortunate to see a few responses, so that is an early sign that this treatment might be efficacious. We certainly think that it is much less toxic than some of the other salvage chemotherapy regimens that are out there, but it is still too early to say what kind of role this will play in salvage regimens for a general, broader audience.

TARGETED ONCOLOGY: What was the rationale for the phase I trial that was presented at the 2019 AACR Meeting?

Navai:HER2 is expressed in a variety of sarcomas, and this is a very difficult-to-treat disease. We initially published a trial in which we used these same CAR T cells without lymphodepletion. The major limitation in that trial was that we saw those CAR T cells did not expand. In this version of the trial, which was led by Meenakshi Hedge, MD, we added lymphodepletion to help improve the expansion. This is what we saw, and fortunately, in this portion of the trial with lymphodepletion, we saw more responses. The main trial, however, was designed just to determine safety, and so far, this seems to be a safe treatment.

TARGETED ONCOLOGY: What are the key findings from this research?

Navai:First, HER2 is a safe target for CAR T-cell therapies. Our CAR uses a different type of antibody than the previously reported trastuzumab-based CAR. In our studies, this has seemed to be a safe target. The other takeaway is that there appears to be some promise for potential efficacy for patients with solid tumors, which is much needed.

TARGETED ONCOLOGY: Although this research is still in early phases, what are the clinical implications of these data?

Navai:For some patients, these types of therapies might be effective, and we need to do further research in terms of which types of patients would benefit. The other research in some of the immune-correlative work that we are doing is showing us some early signs that a patient’s own immune system might be helping make these CAR T cells work, so further research into that to both determine how we can better cause that wakening up as the immune system as well as to determine what the immune system is targeting could help us develop new targets for these therapies.

TARGETED ONCOLOGY: In 5 to 10 years, how do you see the role of CAR T-cell therapy evolving in sarcoma?

Navai:It is hard to say because the pace of advancements in solid tumors has been slow, but my hope is that it will become more of a first-line treatment after standard therapy. I also hope it might be used in the setting of maintenance therapy for patients who have achieved response but are at high-risk for relapse.

TARGETED ONCOLOGY: What take home message would you like to share?

Navai: