November 27, 2016
Immunotherapy is emerging as a promising treatment for certain types of cancer. However, with the current therapies in the clinic, namely checkpoint blockade, responses are limited to a minority of patients, so strategies to further improve immunotherapy are of great interest. A recent study led by MIT PhD student in bioengineering, Hertz Fellow Kelly Moynihan, demonstrated that combining multiple immunotherapies that engage both the innate and adaptive immune responses can completely destroy established tumors in challenging mouse models.
“It was previously unknown whether or not an endogenous immune response could induce complete regression in large, established tumors in these models. We showed that it requires a number of components, but it can be done in a safe manner,” Kelly said. “And we’re excited that this therapy is composed entirely of injectables so you can avoid the costs and scalability concerns associated with adoptive transfer of cells.”
The study, Eradication of Large Established Tumors in Mice by Combination Immunotherapy That Engages Innate and Adaptive Immune Responses
, published by Nature Medicine
in October, is an extension of Moynihan’s previous work on a potent T cell vaccine that achieves lymph node homing by binding to endogenous albumin. Although it generated a powerful immune response and delayed tumor growth, the vaccine didn’t effectively eliminate the tumors on its own. So Kelly and her labmates at MIT’s Koch Institute for Integrative Cancer Research, under MIT bioengineering professor Darrell Irvine, combined efforts with another lab on campus run by Professor Dane Wittrup.
Wittrup’s lab had previously developed a two-part combination immunotherapy, composed of an antibody that binds surface tumor antigen and an engineered cytokine. This therapy relied on many innate immune cells, and it proved effective at significantly slowing the growth of melanoma tumors, but like the vaccine, it did not achieve durable cures.
To this cocktail, the researchers also added the Anti-PD1 checkpoint inhibitor, which blocks signals that would otherwise shut down T cell responses, analogous to taking the breaks off of the immune response. This has shown promise on its own in eliminating melanoma.
“What we’re seeing right now in the clinic is that one correlate of whether people will respond (to the inhibitor alone) is if they have a preexisting immune response that can be awoken by checkpoint blockade,” Kelly said. “The strategy that we’re employing we hope could get around this requirement because we’re generating and supporting an overwhelming anti-tumor immune response, effectively pushing on the gas and taking off the brakes.”
The result was a four-component immunotherapy that acted on both the innate and adaptive arms of the immune system. Tested against melanoma, breast cancer and cervical cancer in mice, the therapy fully eliminated about 75 percent of the tumors.
“People often ignore innate immune effectors when designing immunotherapies, and what we found is if we added in an anti-tumor antibody, we can engage innate cells that express receptors for these antibodies,” Kelly said. “This is what people are excited about; if you can also recruit other immune cells besides just T cells, perhaps immunotherapy can be further improved.”
Previously, effective treatment of large tumors in these models required adoptive cell transfer of T cells, which is expensive, time consuming, and difficult to scale. While this new approach isn’t necessarily going to replace adoptive cell transfer in settings where it’s showing promise, it could prove cheaper and easier to implement, Kelly said.
The next step could see the researchers use the study as a template, substituting other antibodies and vaccines to target different kinds of tumors. Alternatively, developing effective combination immunotherapies without knowing specific tumor targets is of interest, according to an MIT press release.
“I think this is a really exciting finding and we should push forward,” Kelly said.
“Immunofluorescence images show that AIPV combination immunotherapy induces massive infiltration of CD8 T cells into the tumor. Shown are CD8 (green), actin (red), and DAPI (blue) for untreated and AIPV-treated tumors.”