Immunotherapy Combo Shows Long-lasting Responses in Large Mouse Tumors

Immunotherapy Combo Shows Long-lasting Responses in Large Mouse Tumors

Combining immunotherapies to activate both arms of the immune system — the innate and adaptive — can effectively eliminate lymphoma in mice and generate immune cells that recognize new tumor cells that appear long after treatment administration.

The findings, revealed in the study “Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses,” published in Nature Medicine, suggest that the treatment combo may be effective in treating a variety of human tumors, including large tumors that largely suppress immune responses.

“We have shown that with the right combination of signals, the endogenous immune system can routinely overcome large immunosuppressive tumors, which was an unanswered question,” Darrell Irvine, a professor of biological engineering and materials science and engineering, and a member of MIT’s Koch Institute for Integrative Cancer Research, said in a press release.

Although checkpoint blockade therapies have proven that the body’s own immune system can reduce tumor volume, significant responses are seen only in a minority of patients. Researchers believe this happens due to the development of resistance mechanisms to single agents, suggesting that combining several immunotherapy drugs may be key to leading immune responses to their full potential.

Currently, immunotherapies that use three or more drugs are being tested in clinical trials, but positive results in preclinical studies are often obtained by treating very small tumors or treating tumors very early in their development.

In this study, Irvine and Dane Wittrup, the Carbon P. Dubbs professor of chemical engineering and bioengineering and a member of the Koch Institute, sought to assess whether using three immunotherapy drugs plus one targeted therapy could be used to treat large immunosuppressive tumors. And although most studies focus on activating only one of the immune system’s arms, the researchers sought to activate both.

The innate immune system is composed of nonspecific defenses, such as inflammation-inducing molecules, antimicrobial peptides, and cells like macrophages and natural killer cells.

The immune system’s second arm, the adaptive immune system, is composed of T-cells and B-cells, which are specific to a particular antigen (a protein that is recognized by the immune system) and attack cells or pathogens bearing those particular proteins.

Last year, Wittrup found that delivering IL-2, a signaling molecule that helps boost the immune system, combined with delivered T-cells, could stop the growth of aggressive melanoma tumors in mice.

Around the same time, Irvine developed a new type of T-cell vaccine that works by linking a specific antigen found in cancer cells to the blood protein albumin, which gives the antigen a “ride” to the lymph nodes. Once in the lymph nodes, the antigen promotes the production of high numbers of T-cells that target cancer cells.

After seeing the promising effects of each therapy, Irvine and Wittrup decided to combine both immunotherapies to assess whether they induced better anti-cancer responses.

“We had this really good lymph node-targeting vaccine that will drive very strong adaptive immunity, and they had this combination that was recruiting innate immunity very efficiently,” Irvine said. “We wondered if we could bring these two together and try to generate a more integrated immune response that would bring together all arms of the immune system against the tumor.”

In addition to those two immunotherapies, the researchers also included an antibody targeted to the tumor and an anti-PD1 checkpoint inhibitor.

Together, the four agents were expected to generate a stronger and coordinated response:

  • The targeted antibody kills cancer cells and exposes tumor proteins that induce the recruitment of additional innate immune cells that help activating T-cells;
  • The vaccine induces the proliferation of T-cells that are targeted to recognize and kill the tumor cells;
  • IL-2 induces the rapid expansion of T-cells;
  • The anti-PD1 agent helps T-cells stay active for longer periods.

Indeed, when the combination was tested in mice implanted with large, highly immunosuppressive melanoma, lymphoma, or breast tumors, nearly 75 percent of all tumors were eliminated. And when the researchers injected tumor cells into the same mice six months after the therapy, the mice were still able to clear the tumor cells completely.

“To our knowledge, nobody has been able to take tumors that big and cure them with a therapy consisting entirely of injecting biomolecular drugs instead of transplanting T-cells,” Wittrup said.

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