Aiding Immune Responses Through CXCR4 Inhibition in Patients With Pancreatic Cancer

Douglas Fearon, MD

Douglas Fearon, MD

For roughly 10 years, researchers at Cold Spring Harbor Laboratory have been studying the tumor microenvironment in pancreatic cancer. More specifically, they are evaluating how it can prevent a T-cell attack of the cancer cells, said Douglas Fearon, MD.

In a phase I study, Fearon and his colleagues discovered that inhibiting the chemokine receptor type 4 (CXCR4) for one week can activate immune reactions in cancer cells and tumor biopsies. The study also led to the discovery that CXCR4 protects all of the cancer cells and CXCL-12 coats several adenocarcinomas.

Looking forward, a phase II study will test the use of CXCL-12/CXCR4 interaction further by combining CXCR4 inhibition with an anti-PD-L1 checkpoint inhibitor.

In an interview withTargeted Oncologyat the 2019 Ruesch Symposium, Fearon, professor, Weil Cornell Medicine, discussed his presentation on the CXCL-12 pathway, which can exclude T cells from pancreatic ductal adenocarcinoma. He also shared his opinion on how to advance the treatment landscape in the future.

TARGETED ONCOLOGY: What is the prognosis of patients with pancreatic adenocarcinoma?

Fearon: Pancreatic cancer has a disappointing prognosis in that approximately 80% of patients will not be candidates for surgery because they have local invasion of vital structures in the pancreas or distant metastases, and there's currently no medical cure for pancreatic cancer. The 5-year survival rate of those patients is disappointing.

Of the 20% of patients who can have a pancreatectomy, some patients are cured, but the majority end up with metastatic disease appearing within 2 years of surgery. Overall, the prognosis is not good for patients with pancreatic cancer.

TARGETED ONCOLOGY: Can you discuss resistance to therapy including immune checkpoint blockade in patients with pancreatic cancer? What are some of the modern tactics for treating these patients?

Fearon: Immunotherapy has not been successful in any patient with pancreatic cancer other than approximately 2% of patients who have a genetic abnormality that impairs DNA-repair, so-called microsatellite instability. Some of those patients do respond to antibodies directed at the PD-1 checkpoint. Otherwise, immunotherapy has not been as successful in pancreatic cancer as it has in melanoma, non—small cell lung cancer, etc. The majority of patients with adenocarcinoma do not respond to immunotherapy, so it is a common problem.

TARGETED ONCOLOGY: Can you give an overview of your presentation on the pathway that exclude T cells from pancreatic ductal adenocarcinoma?

Fearon: Our lab has been focusing on how the tumor microenvironment prevents a T-cell attack of cancer cells for about 10 years. I reviewed our discovery that fibroblasts are an important immune suppressive cell type in mass models of pancreatic cancer and that the product of the fibroblasts is a chemokine called CXCL-12. We discovered that it mediates the immunosuppression by the fibroblasts. We've conducted a phase I trial in the United Kingdom, which shows that inhibiting the receptor for this chemokine for just 1 week led to the activation of the immune reaction for cancer cells and tumor biopsies. We've discovered that this chemokine coats the cancer cells, and the chemokine CXCL-12 coats all of the adenocarcinomas that we've looked at.

I also presented how the codeine process is mediated and how interrupting the process in a mouse model of liver metastasis makes pancreatic cancer responsive to anti-PD-1 checkpoint therapy.

TARGETED ONCOLOGY: What was the method of design for your phase I study?

Fearon: The small-molecule inhibitor that we used, CXCR4, is clinically approved for another condition. It is given subcutaneously in 1 or 2 injections to release hematopoietic stem cells for the bone marrow. We felt that in our mouse model, it was necessary to continuously inhibit CXCR4, so we gave the small molecule inhibitor intravenously continuously for 1 week.

We also took biopsies of liver metastases before the infusion for 1 week and at the end of the infusion. We then compared the post-treatment biopsy with the pre-treatment biopsy and the expression of immune genes in the biopsies, and that's the way we determined that inhibiting CXCR4 for 1 week in these patients and colorectal cancer patients activated the immune system in the tumor.

TARGETED ONCOLOGY:Where do you see the treatment landscape for pancreatic cancer heading in the next 5 to 10 years?

Fearon: In 2013, we published a mouse study showing that a spontaneous model of pancreatic cancer would respond to CXCR4 inhibition plus an anti-PD-L1 checkpoint inhibitor. Now, here we are 6 years later, and we do not yet have a phase II trial of that combination treatment. So, I'm disappointed that we cannot move more rapidly to translate mouse CXCR4 inhibition with this small molecule, AD3100, plus anti-PD-1 to be conducted at John Hopkins and Dana-Farber Cancer Institute.

I think that this CXCL-12/CXCR4 interaction is important for excluding T cells from tumors. Also, overcoming this inhibitory interaction between CXCL-12, the cancer cell, and CXCL-12 and all immune cells will lead to the majority of adenocarcinomas becoming responsive to anti-PD-1/anti-PD-L1 therapy.

It depends on having available and better CXCR4 inhibitors. The available inhibitors of CXCR4 that are being tested in clinical trials each have drawbacks. It depends on how rapidly we develop better inhibitor of CXCR4.