PICI Makes Progress in Toughest Tumor Types with Pancreatic Cancer Combo, Immune Activity in Cold Tumors

PICI researchers to present on immunotherapy combinations, biomarker data at ASCO Annual Meeting

From a promising combination therapy and a potential predictor of treatment success in advanced pancreatic cancer, to a combination generating immune responses in traditionally cold tumors, researchers from the Parker Institute for Cancer Immunotherapy (PICI) are making progress in pioneering new treatment options for patients battling the toughest types of cancer. They’ll present their findings virtually at the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting.

“We know cancer immunotherapy combinations can be effective for some patients, so it’s critical that we better understand who is most likely to benefit and why,” said Ute Dugan, MD, PhD, PICI’s Chief Medical Officer. “The findings we’re presenting at ASCO can help guide patients, clinicians and researchers alike.”

The work continues to deliver on the promise of Sean Parker’s ambitious vision, and as the organization celebrates its fifth anniversary, here’s a breakdown of PICI research highlights at this year’s ASCO meeting:

Immunotherapy-Chemo Combination Therapy Can Benefit Metastatic Pancreatic Cancer Patients (Abstract #4019)

The combination of standard of care chemotherapy and the PD-1 inhibitor nivolumab – a combination not previously thought to be effective – improved overall survival in metastatic pancreatic cancer in a Phase 2 trial compared to historical data for chemotherapy alone. This includes one patient who experienced a complete response. The trial, called PRINCE, investigated how to activate the immune system to eliminate pancreatic tumors using combinations of chemotherapy, the PD-1 inhibitor nivolumab, and/or an experimental antibody that targets the CD40 protein and activates immune cells.

“The result on the chemo/PD-1 arm particularly surprised us, as the data were more encouraging than observed in a previous early phase trial,” said PICI-supported researcher Mark O’Hara, MD, an assistant professor of Hematology Oncology in the Abramson Cancer Center of the University of Pennsylvania and the study’s lead author.

The study also found adding a CD40 agonist to chemotherapy can activate dendritic and B cells in pancreatic cancer patients, key components of the immune response and showed clinical benefit in some patients. Surprisingly, the combination of both immunotherapies – PD-1 and CD40 – did not improve clinical outcomes compared to historical standard of care data. Importantly, the trial did generate state-of-the-art biomarker data showing that the two immunotherapies, PD-1 and CD40, each had their expected effects on the immune system when individually combined with chemotherapy.

“This shows that different subsets of pancreatic cancer patients may be more likely to respond to chemo and PD-1 versus chemo and CD40,” said Theresa LaVallee, PhD, Vice President of Translational Medicine and Regulatory Affairs at PICI. “Our findings provide clues on how to best identify these patients, and this will inform how we develop combination therapies in the future.”

PICI’s next pancreatic cancer trial, designed with these findings in mind, will launch in the near future.

Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center and a PICI member researcher, is the study’s senior author and the trial’s overall principal investigator.

The study was conducted in partnership with Bristol Myers Squibb, which manufactures nivolumab, and Apexigen, which manufactures sotigalimab, the experimental CD40 agonist used in this trial, as well as the Cancer Research Institute.

Blood Test Can Predict Pancreatic Cancer Patient Response to Therapy (Abstract #4122)

A blood test called a liquid biopsy is also shining light on which pancreatic cancer patients are most likely to respond to immunotherapy. Researchers tested patient plasma at diagnosis and at intervals throughout treatment, specifically looking for the level of circulating tumor DNA that contained mutant KRAS (ctKRAS) – a gene whose mutation is associated with pancreatic tumor growth. Some of these patients were receiving standard of care chemotherapy. Others were enrolled on PRINCE.

The team found that in both cohorts, patients with high ctKRAS levels in their plasma had worse overall outcomes than those whose levels were lower. The study also found that if treatment is able to clear ctKRAS from the blood, patients tend to do better – even if their baseline level was higher. Together, the findings show the potential for liquid biopsy to serve as a biomarker for whether pancreatic cancer patients are likely to respond.

“If a patient is on chemotherapy and liquid biopsy shows ctKRAS levels are staying high, that patient may need to consider other options like a clinical trial. If liquid biopsy shows ctKRAS levels are cleared, it gives that patient and their care team reassurance that the treatment may work,” LaVallee said.

Blood tests are also cheaper than imaging and less invasive than tissue biopsy, so the study also has practical benefits for patient care.

Jacob Till, MD, PhD, a senior research investigator in the Liquid Biopsy Laboratory at Penn and the study’s lead author, will present the findings. Erica L. Carpenter, MBA, PhD, director of the Liquid Biopsy Laboratory at Penn, is the study’s senior author.

In addition to PICI, this work was supported by the National Institutes of Health, the Penn Pancreatic Cancer Research Center, Bristol Myers Squibb and the Cancer Research Institute.

Immunotherapy Combination Can Turn Cold Tumors Hot, Generate Tumor Responses (Abstract #2573)

The combination of the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab may help the immune system recognize tumors that normally stay undetected. PICI’s AMADEUS trial found this combination of checkpoint inhibitors has the ability to drive CD8 T cells into a wide variety of tumors with low levels of CD8 T cells at baseline – which are also known as “cold” tumors. It also showed that driving these T cells into cold tumors – turning them “hot” – can lead to clinical responses.

“This study may provide clues about how we can enable CD8 T cells to infiltrate and eliminate tumors,” said Marko Spasic, MD, Medical Director at PICI and a co-author on the study. “By better understanding the relationship between the effects of immunotherapy and a patient’s own immune characteristics, we can learn how the interaction between the two drives clinical responses.”

This is also a study that draws deeply from the historical work of PICI’s network of researchers. Senior author Padmanee Sharma, MD, PhD, professor and co-director of PICI at The University of Texas MD Anderson Cancer Center, led the work and has been researching the relationship between T cell infiltration and immune responses throughout her career. Co-author James P. Allison, PhD, professor and co-director of PICI at MD Anderson Cancer Center, pioneered CTLA-4 checkpoint inhibitors and won a Nobel Prize for his work in this area.

The study’s lead author, Apostolia Tsimberidou, MD, PhD, PICI-supported researcher and professor at MD Anderson, will present the findings. Additional partners on this work include Bristol Myers Squibb, which manufactures nivolumab and ipilimumab, and the Cancer Research Institute.