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Gradalis' Autologous Immunotherapy Shows Promise in Certain Ovarian Cancer Patients


NEW YORK – Gradalis is pursuing a more personalized approach to immunotherapies with an engineered autologous tumor cell immunotherapy for ovarian cancer that will enter a Phase III trial next year.

The Carrollton, Texas-based company published a retrospective study last month exploring predictive biomarkers of response for its immunotherapy, gemogenovatucel-T or Vigil, as a maintenance therapy for newly diagnosed ovarian cancer. The paper, published in Communications Medicine, found that high expression of the immune marker ENTPD1/CD39 could identify which patients respond to Vigil.

Researchers from Gradalis and several cancer centers performed a retrospective analysis of tissue samples from 91 patients with late-stage high-grade papillary serous or clear cell endometrioid, ovarian, fallopian tube, or primary peritoneal cancer, who received Vigil or placebo as maintenance treatment within a Phase II trial. They also used the NanoString PanCancer Immuno-Oncology 360 panel to analyze expression of more than 750 genes in patients' samples.

John Nemunaitis, senior study author and Gradalis CSO, said his team set a very high threshold of statistical significance in the study to ensure that any biomarkers identified in the analysis were associated with both overall survival and relapse-free survival for these newly diagnosed patients.

"In setting the bar that high, we came up with only one signal that demonstrated statistical significance and that was ENTPD1 or CD 39," he continued. "That signal demonstrated a benefit in relapse-free survival and overall survival. It was a very encouraging and highly significant factor in guiding us to the most sensitive group of ovarian cancer patients that potentially would have the best response to this Vigil therapy."

The analysis grouped patients from both the Vigil arm and the placebo arm of the trial into high or low ENTPD1/CD39 expression. They found that high expression of ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), also known as CD39, was correlated with improved overall survival and relapse-free survival on Vigil compared to low CD39 expression.

At three years, twice as many CD39-high patients were alive than CD39-low patients in the Vigil arm, eight patients and four patients, respectively. CD39-high patients were also less likely to experience a relapse on the immunotherapy. At one year, 12 CD39-high patients had not relapsed on Vigil compared to five CD39-low patients. At three years, there were two CD39-high patients and one CD39-low patient who had not yet relapsed on treatment.

In the Vigil arm, the CD39-high group did not reach overall survival with four years of follow-up compared to a median overall survival of 27 months in the placebo arm. Median relapse-free survival in the CD39-high group was 21.1 months on Vigil versus 5.6 months on placebo.

Nemunaitis explained that Vigil is designed to perform three functions to target cancer cells. The treatment is similar to an autologous CAR T-cell therapy where samples are taken from patients, engineered to target cancer cells, and then reintroduced into the same patient. But instead of modifying immune cells like a CAR T-cell therapy, Vigil alters tumor cells.

During the manufacturing process, the company modifies patient's cancer cells to target neoantigens present in their tumor, downregulate certain immunosuppressive pathways, and stimulate immune function of their cells. Unlike one-time CAR T-cell therapy, Vigil is given as a monthly injection. However, the patient's tumor cells are only collected once, and those original samples are used for each subsequent treatment with Vigil. The tumor tissue samples are frozen and shipped to Gradalis' manufacturing facility. The manufacturing process takes two days, according to Gradalis, and up to 12 doses of Vigil can be produced for each patient.

"We put a plasmid in [Vigil] that carries DNA signals that help the immune system recognize the cancer," Nemunaitis said. The signals facilitate knockdown of the cytokines TGF-beta 1 and TGF-beta 2, and decreasing the levels of these cytokines helps prevent the cancer from inhibiting the immune system, he explained.

The therapy also increases expression of GMCSF, a gene that's involved in activating the immune system and helping it to recognize cancer cells by identifying the patient-specific neoantigens in the cancer.

"The immune system, over a number of months [of treatment], changes to where now it provides trillions of activated immune T cells and B cells that travel throughout the body to find the cancer," Nemunaitis said.

The latest research identifying high CD39 expression as a predictive biomarker can now be combined with a previous study showing that ovarian cancer patients with homologous recombination proficient (HRP) status benefited from Vigil.

Next year, Gradalis will begin a Phase III registrational trial of Vigil as a maintenance therapy for newly diagnosed HRP ovarian cancer patients. The study design is still in the works, but Nemunaitis said it will likely compare Vigil plus Genentech's Avastin (bevacizumab) against Avastin alone. They will also assess patients in that trial for ENTPD1/CD39 expression and prospectively analyze whether that signal continues to identify best responders.

If that trial is positive, Vigil plus Avastin could become the new standard of care for maintenance treatment for HRP ovarian cancer patients, he added. HRP status patients often have limited treatment options because most PARP inhibitors are intended for homologous recombination deficient or BRCA1/2-mutant patients.

While PARP inhibitors have shown to improve relapse-free survival in some HRP ovarian cancer patients, Nemunaitis said there haven't been studies showing these drugs extend overall survival for this population.

"We have targeted Vigil in just the HRP patients, which is about 50 percent of all ovarian cancer patients," he said. "Vigil's advantage in overall survival, as well as progression-free survival and relapse-free survival, is very encouraging. We feel that Vigil would likely be the mainstay in the HRP patients if the trial is positive."

Outside of ovarian cancer, Gradalis is also evaluating Vigil as a treatment for breast cancer and Ewing's sarcoma. The ENTPD1/CD39 signal identified in the latest research could also guide how the company develops Vigil in these and other cancer types.

"If [ENTPD1/CD39 expression] continues to show what it showed in the retrospective analysis published in Communications Medicine, then we will use that signal to guide us in the direction to go with Vigil," Nemunaitis said. "We could use it as an indicator not only for ovarian cancer but also for other cancers. We believe that it will be a significant factor, and it'll help us target Vigil to the most responsive patients."