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Penn Scientists Testing Out CAR T-Cell Therapy Gel to Prevent Breast Cancer Recurrence Post-Surgery

Fibrin glue for surgery

NEW YORK – Researchers at the University of Pennsylvania are gearing up for a trial investigating an intriguing approach to solid tumor CAR T-cell therapy: delivering the modified cells in a gel-like substance during surgery.

The Phase I trial, expected to launch during the fourth quarter of 2023, will enroll roughly 18 patients with locally advanced triple-negative breast cancer who are eligible for surgical resection. The autologous CAR T-cell therapy is designed to target mesothelin on the surface of tumor cells, and patients' tumors must express mesothelin, as detected via immunohistochemistry testing, to partake in the trial.

As Carl June, the director of UPenn's Center for Cellular Immunotherapies and Parker Institute for Cancer Immunotherapy, explained it, in the week leading up to surgery, patients will have their blood drawn, from which the starting material for the CAR T-cell therapy will be harvested. Then, over roughly three days of manufacturing, the T cells harvested from the patient are engineered to express a chimeric antigen receptor targeting mesothelin. Before patients undergo surgery, the autologous, mesothelin-specific T cells are mixed into a fibrin gel. This glue-like substance, which is already approved by the US Food and Drug Administration to facilitate wound healing during surgery, can be applied directly to the site where the breast cancer tumor was resected during surgery.

Roughly 10 days after surgery, patients will undergo a scheduled biopsy. "Other than those procedures, patients will receive standard of care," June said, explaining that from the perspective of the patient, who would already be undergoing surgical tumor resection, the only additional aspects of the treatment regimen include the initial blood draw and follow-up biopsy.

The primary goal of the upcoming UPenn-sponsored trial will be to establish this treatment's safety, with a special emphasis on exploring the rate of cytokine release syndrome among patients and any negative effects that the treatment might have on surgical wound healing. June acknowledged that there are details that the investigators are still ironing out, including how to factor in the availability of adjuvant immunotherapy treatments for locally advanced TNBC patients into the trial's eligibility criteria. 

Preclinical evidence, rationale

Last week, June and colleagues published a paper in the journal Science Advances detailing the in vivo preclinical experiments that gave them the confidence to move into human trials. In mouse models of both TNBC and pancreatic cancer, two tumor types that commonly express mesothelin, the researchers found that administering CAR T cells within the fibrin gel during surgery effectively eliminated any remaining cancer cells while reducing adverse events and toxicities that solid tumor patients on CAR T-cell therapies typically experience.

The reason for this, June said, is that the fibrin gel allows the CAR T cells to migrate out of the gel enough to kill the tumor cells in the surgical area but prevents the cells from fully migrating out of the local area and into the patient's bloodstream. This is important because the mesothelin target can be expressed on healthy cells elsewhere in the body, including in lung tissue. If the CAR T cells migrate away from the tumor site to a significant extent and attack these healthy mesothelin-expressing cells, it can cause significant on-target off-tumor toxicity.

"There is a low-level escape into the bloodstream in some mice," June said of the CAR T cells in the preclinical study. "However, we don't think this will be a safety issue because that is very different from an intravenous bolus of cells that passage directly by bloodstream into the lungs."

In other words, if the mesothelin-targeting CAR T cells were to be infused into the patient systemically via an IV, as is the usual mode of administration for cell therapies, far more of the CAR T cells would likely end up attacking healthy tissue on their journey through the body to the residual mesothelin-expressing tumor cells at the surgical site.

"A major limitation of the use of CAR and TCR T cells for solid tumors has been on-target off-tumor toxicity," June and colleagues wrote in the Science Advances paper. "Retention of CAR T cells at the surgery site may increase safety by decreasing systemic toxicity."

In the mouse models, June and his team also went through several control experiments to make sure the CAR T-cell therapy within the fibrin gel had an advantageous effect. For instance, they tried administering the mesothelin-directed CAR T cells directly into the resected tumor site without the gel and found that seven out of 10 mice experienced cancer recurrence after their surgery. Meanwhile, all of the mice that received the CAR T cells in the fibrin gel administered at the surgical site experienced complete tumor regression, and then went on to experience significantly longer overall survival.

The researchers also tried to administer CD19-directed CAR T cells in fibrin gel and found that the tumors progressed here, too. Additionally, they administered just the fibrin gel itself, without the CAR T cells, to the post-surgery site in the mice to make sure the gel was not responsible for the improved effect and confirmed that it was not. Ultimately, in mouse models with both TNBC and pancreatic cancer, it was specifically the mesothelin-directed CAR T cells in the fibrin gel mixture that eliminated residual tumor cells and prevented cancer recurrence.

While June and colleagues are hoping to eventually test the approach in pancreatic cancer clinical trials, they are beginning the human studies with TNBC only. "We decided to first start in TNBC because the biopsies on chest wall recurrences are safer," June said.

Ultimately, if the upcoming Phase I trial demonstrates that the approach is safe, the researchers see potential for the approach in other solid tumor types such as ovarian and lung cancer. And for those patients who don't express mesothelin, the researchers hope to use a similar approach to target other cell-surface proteins like HER2, MET, CEA, or MUC1.

If this gel-like formulation of CAR T-cell therapy were ever to be commercially available for patients undergoing surgical resection, June said its manufacturing ease would be a key advantage. The changes to the process would be "almost trivial" versus that which is already used to manufacture CAR T-cell therapy without the fibrin gel. Indeed, the gel is already available in ready-to-use pre-filled syringes, which the researchers purchased from the company Baxter for their preclinical studies. Additionally, mixing the CAR T-cell therapy into the gel could be done in the operating room.

According to June, the Science Advances paper demonstrates the anti-tumor potential for this new CAR T-cell formulation, and, if successful, he envisions this may be used as an add-on to surgery for solid tumors and potentially even combined with other anticancer therapies after surgery.