Immuno-Oncology Resource Center

Immuno-Oncology Resource Center

Source:

Chen S, et al. Tackling the toughest challenges — pancreatic cancer. Presented at: Alliance for Cancer Gene Therapy Summit (virtual meeting); April 29, 2021.

Disclosures: No products or companies that would require financial disclosure are mentioned in this article.
May 14, 2021
4 min read
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Cell therapy part of the solution to curing pancreatic cancer, experts say

Source:

Chen S, et al. Tackling the toughest challenges — pancreatic cancer. Presented at: Alliance for Cancer Gene Therapy Summit (virtual meeting); April 29, 2021.

Disclosures: No products or companies that would require financial disclosure are mentioned in this article.
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Cellular therapies will play a key role in pancreatic cancer management despite challenges thus far in applying these treatments to solid tumors, according to a panel discussion during the virtual Alliance for Cancer Gene Therapy Summit.

Pancreatic cancer will account for about 3% of all cancer diagnoses in the U.S. this year. However, more than 50,000 Americans will die of the disease, making it the third most common cause of cancer-related mortality, according to Andrew Rakeman, PhD, vice president for research at Lustgarten Foundation.

Sidi Chen, PhD, assistant professor in the department of genetics and Systems Biology Institute at Yale School of Medicine and member of Yale Cancer Center.

“There is a need for new ideas and new approaches to treating pancreatic cancer,” he said.

The numerous challenges in pancreatic cancer treatment have been well-documented and available immunotherapies have not had the impact on this disease that researchers had hoped, Rakeman said.

“In the years to come, I think you will see us address those specific challenges,” Rakeman said. “Pancreatic cancer may be on the brink of meaningful therapeutic breakthroughs thanks to advances in cellular therapy.”

Despite the poor prognosis for patients with pancreatic cancer, cellular therapies and combinatorial strategies under investigation portend a brighter future, according to fellow panelist Mark OHara, MD, assistant professor of medicine in the division of hematology and oncology at University of Pennsylvania’s Abramson Cancer Center.

Mark O’Hara, MD
Mark O'Hara

“I feel like we are on the brink of something that will change the management of pancreatic cancer,” he said. “There is a lot of work being done in this field that has promise, so I am going to put my hat in that basket for now.”

A ‘highly evolved’ disease

Advances in cellular therapy have created a “terribly exciting time” in the field of pancreatic cancer research, according to Michael T. Lotze, MD, PhD, professor of surgery and bioengineering at University of Pittsburgh.

“Cell therapy efforts will be the ones to pay off because single small-molecule drugs are not capable of changing what is a highly evolved malignant lesion,” Lotze said.

His remarks highlighted one of the many challenges associated with pancreatic cancer treatment — the disease often is associated with genetic mutations that have not been successfully targeted with current immunotherapies.

“We won't cure cancer without the use of T cells, but T cells themselves are not enough,” Lotze said. “We need to find ways to facilitate getting T cells into the pancreatic tumor microenvironment.”

Another established challenge to treating pancreatic cancer involves diagnostics, according to Sidi Chen, PhD, assistant professor in the department of genetics and Systems Biology Institute at Yale School of Medicine and member of Yale Cancer Center.

“When we find it, pancreatic cancer is almost always in its late stages,” he said, noting the disease’s highly metastatic nature makes it more difficult to treat. In addition, immune checkpoint inhibitors — which have revolutionized treatment of solid tumors — have yet to substantially extend survival or improve quality of life for patients with pancreatic cancer.

“We need new, transformative approaches to make a difference,” he said. “Cell therapy is one of the most powerful approaches we can use.”

Chen’s lab is working on ways to improve the immune system’s ability to recognize cancer cells.

“We believe that the best way to cure cancer is to kill all of the cancer cells but spare all of the healthy cells,” he said. “Of course, this is a dream situation, but the more we can distinguish abnormal cells from healthy cells, the better off we will be.”

To that end, Chen said his group is looking to devise a cell therapy-based system that allows the body’s immune system to attack cancer cells while leaving healthy ones unscathed.

Improving on the early days of CAR-T

Current treatment for pancreatic cancer that cannot be successfully resected includes multiple rounds of chemotherapy. This strategy that lacks efficacy and results in many adverse effects, O’Hara said. He agreed that immune checkpoint inhibitors used for other cancers are “largely ineffective in pancreatic cancer.”

His research focuses on bringing novel immunotherapies to pancreatic cancer through clinical trials and examining CAR T cells alone or in combination with other therapies to learn about how they interact.

Cell therapies often are given as single agents when a patient has advanced disease and no alternative treatments are available, O’Hara said. This traditionally follows unsuccessful rounds of chemotherapy and immunotherapy, with the latter showing diminishing effectiveness after chemotherapy.

O’Hara advocated for an approach that involves induction chemotherapy for 4 to 6 months followed by novel immunotherapies, including cell therapy. The hope is that controlling the disease first and decreasing the tumor burden can increase the efficacy of CAR T-cell therapy.

“I am a strong advocate for the combinatorial approach because single agents produce hardly any results,” Chen said. “Combining immune gene therapy plus immune checkpoint inhibitors plus cellular therapy could help us solve the problem.”

Chen’s group is examining the use of gene editing to “silence” the expression of mutations such as KRAS, which is highly prevalent among patients with pancreatic cancer but has proved difficult to target with existing therapies.

“Rather than targeting the oncogene, activating the immune system to chase oncogenic cancer cells and form T-cell memory is a more realistic approach,” Chen said. “If we can educate the immune system to form the memory T cells and B cells that can recognize mutated cancer cells, then it may be a more feasible way to target cancer cells with KRAS mutations or other highly aggressive forms of cancer, such as pancreatic cancer.”

Research from the NIH has identified a group of T-cell receptors that can recognize mutated KRAS variants, according to Joseph Fraietta, PhD, assistant professor of microbiology and director of the solid tumor immunotherapy laboratory in the Center for Advanced Cellular Therapeutics at University of Pennsylvania’s Abramson Cancer Center. The variants noted by the NIH researchers cover most KRAS driver mutations expressed by a variety of epithelial cancers, including pancreatic cancer, Fraietta added.

Fraietta also briefly mentioned the promise of tumor-infiltrating lymphocytes for treating solid tumors.

“I have a lot of hope for these strategies,” he said.

Fraietta advocated for use of cellular therapies “as a lead-in approach to tackle the immunosuppressive tumor microenvironment” followed by combinatorial therapies that attack tumor cells.

“But first, we need an effective CAR T-cell therapy against solid tumors,” he said.

“We are in the early days of using CAR T cells for pancreatic cancer, but it is something that has shown some promise,” Fraietta said. “Some of the CAR T cells we have evaluated have shown signs of efficacy. I think we just need to bolster that activity by combining it with other therapies.”

References:

Chen S, et al. Tackling the toughest challenges — pancreatic cancer. Presented at: Alliance for Cancer Gene Therapy Summit (virtual meeting); April 29, 2021.
Sim MJW, et al. Proc Natl Acad Sci U S A. 2020;doi:10.1073/pnas.1921964117.