Making Pancreatic Cancer a Target for Immunotherapy
June 18, 2014 |
Some cancers are known to be highly immunogenic—that is, able to provoke an immune response. Melanoma, kidney cancer, and non-small cell lung cancer are three such immunogenic cancers. Not coincidentally, these are also the cancers that have responded most dramatically to existing immunotherapies, such as checkpoint inhibitors. Because the immune system has already recognized these cancers, this pre-existing immune response can be strengthened with immunotherapies, generating a more powerful anti-cancer response.
Other tumor types are notoriously resistant to immunotherapies, pancreatic cancer being the prime example. Researchers have shown, for example, that treating pancreatic cancer patients with the checkpoint inhibitor ipilimumab (Yervoy®) as a single agent does not improve survival—in striking contrast to the situation with melanoma and other immunogenic tumors.
But what if there were a way to jumpstart an immune response to pancreatic cancer? Could this cancer type then become a potential target for immunotherapies—in particular, the promising anti-PD-1 checkpoint inhibitors that are currently making such waves in the oncology community?
Researchers at the Johns Hopkins School of Medicine have now begun to crack this nut. In a paper published today in the journal Cancer Immunology Research, Lei Zheng, M.D., Ph.D., CRI Scientific Advisory Council member Elizabeth Jaffee, M.D., and colleagues show that administering a therapeutic cancer vaccine known as GVAX to patients with pancreatic cancer can trigger an immune response to the cancer. In particular, the authors show that the vaccine triggers recruitment of tumor infiltrating lymphocytes (TILs) to the site of the tumor.
Normally, in unvaccinated patients, pancreatic tumors have very few lymphocytes present; indeed, this immune ghost town provides the explanation why the tumor is non-immunogenic. But just 2 weeks after a single intradermal injection of GVAX, pancreatic tumors show populations of TILs. Moreover, these TILs show molecular signs of being activated against pancreatic tumor antigens. In effect, the researchers have shown that pancreatic cancer can be converted from a non-immunogenic tumor type to an immunogenic one. As the authors note, these promising results raise the possibility that pancreatic cancer could be treated with immunotherapies that combine, for example, cancer vaccines and checkpoint inhibitors.
In fact, such clinical trials are already under way. At Hopkins, a phase 1b trial combining GVAX and ipilimumab showed that the combination was more effective at improving survival than ipilimumab alone (which was without benefit). What this new study does is provide a clear explanation for this clinical picture.
“Our study shows for the first time that treatment with a vaccine-based therapy directly reprograms the pancreatic cancer microenvironment, allowing the formation of lymphoid aggregates, which are organized, lymph node-like, functional immune structures, and which convert an immunologically quiescent tumor into an immunologically active tumor,” Zheng said.
There were other noteworthy findings. In particular, the team discovered that GVAX stimulated not only cancer-fighting “killer” T cells to migrate to tumors, but also recruited regulatory T cells (Tregs) to the tumor battleground. Tregs are a type of immune cell that serve as checks and balances on the immune response. It is the balance between killer T cells and Tregs, in part, that determines the strength and durability of an immune response. The presence of Tregs in tumors after GVAX treatment suggests why vaccine therapies do not by themselves lead to dramatic therapeutic effects in pancreatic cancer—the incipient immune response is prematurely squelched.
What if Tregs could be removed from the tumor site? To test whether the immune response against pancreatic cancer could be enhanced by removing Tregs, the researchers administered the chemotherapy drug cyclophosphamide (Cy), known to preferentially kills off Tregs. They found that Cy indeed shifts the balance of T cells in the tumor microenvironment toward killer T cells, suggesting that this drug might be combined effectively with GVAX to enhance an immune response.
The third piece of the puzzle, needed to fully unleash a powerful immune response against cancer, would be an immune-modulating agent such as a checkpoint inhibitor (anti-CTLA-4 or anti-PD-1, for example) that would “take the brakes” off the T cell response. Then, researchers hope, we might see in pancreatic cancer what we have seen so far in melanoma and other cancer types: dramatic tumor regressions and durable, life-saving remissions.
To learn more about immune therapy for pancreatic cancer, tune in to a Twitter chat on the “Promise of Immunotherapy,” Wednesday June 18, from 1:00 p.m. - 2:00 p.m. EDT hosted by CRI, Mayo Clinic, AACR, and TIME magazine.
Lutz ER et al., (2014) Immunotherapy Converts Nonimmunogenic Pancreatic Tumors into Immunogenic Foci of Immune Regulation. Cancer Immunol Res;
Published Online First June 18, 2014; doi:10.1158/2326-6066.CIR-14-0027