A new combination of immune agonists has shown impressive results in targeting the remarkably treatment-resistant pancreatic ductal adenocarcinoma cancer (PDAC). While many forms of cancer have responded remarkably well in recent years to various immunotherapies, PDAC has shown poor responsiveness. It is thought that PDAC builds an unusually resilient cocoon of fibrous desmoplastic tissue around the tumor that impedes the ability of T cells or drug-activated antibodies to penetrate the tumor, while establishing a favorable microenvironment around the tumor that enables it to thrive.
The Abramson Cancer Center of the University of Pennsylvania has been recognized as a global leader in exploring ways that the CD40 agonist antibody helps to teach and activate T cells to respond to tumor fragments in a number of cancers. Their research found, however, that CD40 was ineffective against PDAC, which has emerged as the fourth most lethal kind of cancer in the United States, with only 5 to 20 percent of people diagnosed living beyond five years, depending on the stage of their disease at the time of diagnosis.
Meanwhile, Dr. Nandita Bose, a principal in translational immunology and R&D at Biothera Pharmaceuticals, thought the company’s Imprime PGG might be an effective partner with CD40 to pump up the innate immune response. Because the myeloid cells of PDAC restricted the efficacy of CD40, Bose and Dr. Gregory Beatty from UPenn felt the addition of a second myeloid agonist could amp up immune response.
“Collectively, these data show that systemic Imprime PGG therapy can remodel the normally immunosuppressive tumor microenvironment and enhance the effectiveness of checkpoint inhibitor therapy,” according to Biothera. As per a poster presented at the recent Keystone Symposia in Canada, the combination of Imprime PGG and a CD40 agonist antibody induced complete and durable regressions in a majority of mice. Tumor-free mice also resisted tumor re-challenge, suggesting the establishment of immune memory. This therapeutic effect was completely abrogated by CD4/CD8 cell depletion, indicating that the combination of Imprime PGG with the CD40 agonist worked by activation T cell-based immunity.
Initial tests were conducted via implantable tumor models in mice that have a history of responding well to CD40 antibodies. The next step, however, will be to test the combination in spontaneous PDAC tumors in mice to measure the response. CD40 has not performed as well in spontaneous models in general, and with the added challenge of the two permeating the desmoplastic cocoon, the spontaneous study will provide guidance on next steps, perhaps by defining subsets or suggesting instances when response will be best.
“We are not sure if Imprime PGG is unique—there may be other agonists that will work with CD40—but the fact that we have two clinically available compounds that appear to prime immune response to PDAC is very exciting,” says Beatty. “The activity of this combination is quite striking and warrants further investigation.”
Beatty stresses that human clinical trials are not yet planned, as researchers must first explore the results of the application on spontaneous tumors and await a positive response. They can then ferret out the molecular mechanisms for why the two molecules have such effective symmetry and deepen the understanding of the symbiotic relationship.
Pending more positive results, researchers may apply the combination to judge effectiveness in treating other cancers that do not respond well to checkpoint inhibitors like CD40, such as colorectal cancer, liver cancer and other gastric cancers. While the reasons these cancers do not respond as well to CD40 or other immunosuppressants varies, a functional symbiosis opens the door for promising research in other cancer studies.
“The study has brought together two compounds with tremendous potential,” comments Beatty. “My hope is that it will pave the way for a bridge between industry and academia that will leverage the potential and initiate trials that will ultimately make a difference for patients diagnosed with pancreatic cancer.”