New research aims to crack CAR-T solid tumor code in ovarian cancer
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Researchers from City of Hope have detailed results of preclinical studies designed to optimize the durability of chimeric antigen receptor T cells for advanced ovarian cancer.
The findings — published in Nature Communications — aim to enhance future iterations of a novel CAR-T construct being evaluated in a first-in-human clinical trial.
CAR T cells have “proven to be more than just a one-hit wonder,” Saul J. Priceman, PhD, associate professor in the department of hematology and hematopoietic cell transplantation and associate director of translational sciences and technologies in the T Cell Therapeutics Research Laboratories at City of Hope, told Healio.
“It has been my mission — along with many others in and outside of City of Hope — to develop these types of therapies for solid tumors,” he added. “Our lab is actively looking for ways to improve CAR T-cell therapy and, despite the challenges, we won’t give up. We are ‘all in’ on this, and it’s for the benefit of our patients.”
Priceman spoke with Healio about the CAR-T’s development, what they are evaluating in the phase 1 study, and how his lab’s latest investigations may improve outcomes for women with advanced ovarian cancer.
Healio: Can you describe your rationale for using CAR-T to treat ovarian cancer?
Priceman: Ovarian cancer is unique from other cancer types considered to be ‘immunologically cold,’ such as prostate cancer or pancreatic cancer. These cancers typically do not elicit a noticeable immune response. There is anywhere from suboptimal to no recognition by the immune system of cancer within the body, which means no active immune response trying to eradicate the disease. In ovarian cancer, a subset of patients respond to immune checkpoint blockade, and we have learned over the past decade that patients who are responsive to immunotherapy also may be responsive to CAR T-cell therapy. So, although we have experienced many challenges treating prostate cancer and pancreatic cancer with immunotherapy, we reasoned that ovarian cancer may be a bit more responsive. These tumors tend to be a little more immunologically warm and may benefit from immunotherapy and — in particular — cellular immunotherapy or CAR T cells.
We did not anticipate this would become a clinical candidate but — because the preclinical studies were so promising — we advanced regional intraperitoneal administration of these T cells, which showed potent and dramatic antitumor responses in our preclinical models. The positive results from those studies left us with no choice but to embark on identifying a clinical candidate for optimizing the therapy toward human studies. That led us to our early-stage clinical trial evaluating this CAR T-cell therapy for patients with advanced ovarian cancer.
Healio: Why did you choose locoregional administration of this CAR-T?
Priceman: Most patients with ovarian cancer have peritoneal involvement, which means the disease has left the ovaries or fallopian tubes and spread to the peritoneum. This type of disease carries a very poor prognosis.
The process was iterative. We didn’t know we ultimately would regionally administer CAR T cells to patients with advanced ovarian cancer, but that became something we took advantage of because of our institution’s experience with regional administration of [modified] T cells for other diseases.
Clinically, we’ve taken an optimized CAR T cell that targets tumor-associated glycoprotein-72 (TAG72) — which is a modification that uniquely occurs in cancer cells — to target TAG72-positive ovarian cancers. Our peritoneal regional administration of those CAR T cells has been translated to the clinic, and that’s how we are treating patients now.
Healio: Can you explain the results of the preclinical study your group published in Nature Communications?
Priceman: The publication was a vignette of various preclinical findings. In a previous clinical study, we validated TAG72 as a target for ovarian cancer. This was followed by important findings showing dramatic responses when we administered the CAR-T intraperitoneally. In that same publication, we noted that the therapy — although it was potent and showed a very immediate eradication of tumors — was not durable. Those tumors all came back.
Since then, our lab has systematically optimized the TAG72-directed CAR-T being evaluated in the phase 1 trial, and that comprised part of the findings we reported. The remainder of the publication focused on our efforts to address limited trafficking of CAR T cells outside the injection site area when administered locally, which has emerged as a challenge in treating solid tumors with CAR-T. Our experience has shown this to occur when regionally administering CAR T cells into the brain or the peritoneal cavity, as the cells identify a tumor in the region and stay within the cavity without migrating out. This is unfortunate for patients with breast cancer-related brain metastases or peritoneal ovarian cancer.
Our lab engineered the CAR T cells to express the cytokine interleukin (IL)-12 in a very specific manner. Cytokines usually are secreted outside of the cell and travel within the body. Our lab developed a construct that literally tethered IL-12 physically to the surface of the T cell. The IL-12 in our CAR T cell was restricted to acting on the T cell or in small neighborhoods around it.
IL-12 is a potent cytokine that can be very toxic within the body. Our tethered approach of putting the IL-12 on the surface of the T cell was safe in all of our preclinical models, in addition to being very potent and improving CAR T-cell therapy responses. Most importantly, it enabled the trafficking of those T cells from the regional site of delivery outside to other places in the body to treat bone and metastatic disease. To us, that is a very big improvement in our regionally administered CAR T cells.
Healio: Did you find any toxicities associated with either IL-12 tethering or targeting TAG72?
Priceman: In the preclinical setting, we observed severe toxicities when IL-12 was administered systemically in the host (body), which is consistent with the reported clinical use experience of IL-12. Our tethered approach showed no toxicities, with a similar and perhaps even superior therapeutic benefit than if the cytokine had been systemically administered. This finding occurred in preclinical testing, and it remains to be seen if this safety performance will be consistent in the clinical setting — but we have high hopes.
As for the TAG72 CAR T cell that’s now in the clinic, it is very early. Only a couple patients have been treated and the trial is ongoing, but so far we haven’t seen any negative effects.
Healio: Are there plans to apply knowledge from these studies into an intervention that improves CAR-T efficacy?
Priceman: Part of what we published already has been translated into our active phase 1 trial. Our group is now actively translating the IL-12 engineering approach, with plans to open a trial within the next 2 years. Right now, decisions are being made about what disease setting best fits the therapy and how to translate it most rapidly to patients.
References:
- Lee EHJ, et al. Nat Commun. 2023;doi:10.1038/s41467-023-40115-1.
- Murad JP, et al. Front Immunol. 2018;doi:10.3389/fimmu.2018.02268.
For more information:
Saul J. Priceman, PhD, can be reached at spriceman@coh.org.
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