Dead tumor cells have been researched as potential adjuvants for cancer vaccines and immunotherapies, but new experiments in mice, headed by researchers at MIT, have demonstrated that a patient’s own live tumor cells, damaged by chemotherapy, may also augment antitumor immunity. The results suggest these live cell adjuvants may enhance the effectiveness of immune checkpoint blockade (ICB) in tumors that wouldn’t normally respond to such treatment alone.
The novel approach involves removing tumor cells from the body, treating them with chemotherapy drugs, and then placing them back in the tumor. When delivered along with drugs that activate T cells, these injured cancer cells appear to act as a distress signal that spurs the T cells into action. In vivo tests reported by the MIT team showed that this approach could completely eliminate tumors in nearly half of the treated mice. The researchers hope that this new way to jump-start the immune system to attacking tumors could allow the use of immunotherapy against more types of cancer.
“When you create cells that have DNA damage but are not killed, under certain conditions those live, injured cells can send a signal that awakens the immune system,” says Michael Yaffe, PhD, who is a David H. Koch Professor of Science, the director of the MIT Center for Precision Cancer Medicine, and a member of MIT’s Koch Institute for Integrative Cancer Research. “Our findings fit perfectly with the concept that ‘danger signals’ within cells can talk to the immune system, a theory pioneered by Polly Matzinger at NIH in the 1990s, though still not universally accepted.”
Yaffe, and Darrell Irvine, PhD, who is the Underwood-Prescott Professor with appointments in MIT’s departments of Biological Engineering and Materials Science and Engineering, and an associate director of the Koch Institute, are senior authors of the team’s published report in Science Signaling, which is titled “The injury response to DNA damage in live tumor cells promotes antitumor immunity.”
Cytotoxic chemotherapy remains a mainstay of cancer treatment, but while conventional chemotherapy drugs can extend survival and even cure some types of cancer, they can have toxic side effects, and tumors may develop resistance, resulting in relapse. Immunotherapy has emerged as a promising strategy to treat cancer by stimulating the body’s own immune system to destroy tumor cells, but it only works for a handful of cancers. One class of drugs currently used for cancer immunotherapy is checkpoint blockade inhibitors, which take the brakes off of T cells that have become “exhausted” and unable to attack tumors. But while these drugs have shown success in treating a few types of cancer, the do not work against many others.
“It has been estimated that the overall percentage of all patients with cancer who will respond to immune checkpoint inhibitors alone is less than 13%,” the authors wrote. And while treatment that combines chemotherapy and immune checkpoint inhibition has recently been approved as first line therapy for some types of advanced cancers, “… for many tumor types, immunotherapy has been reserved as a second- or third-line treatment option in patients who have failed prior treatment with cytotoxic agents,” the team continued. “Identifying mechanisms that would enhance response rates to the combination of immune checkpoint blockade (ICB) and chemotherapy—and prolong the durability of the response—remains an unmet clinical need.”
Yaffe and his colleagues set out to try to improve the performance of these drugs by combining them with cytotoxic chemotherapy drugs, in hopes that the chemotherapy could help stimulate the immune system to kill tumor cells. This approach is based on a phenomenon known as immunogenic cell death, in which dead or dying tumor cells send signals that attract the immune system’s attention.
Several clinical trials combining chemotherapy and immunotherapy drugs are under way, but little is known so far about the best way to combine these two types of treatment. “On the basis of our long-standing interest in cross-talk between the DNA damage response and signaling pathways that mediate tumor cell survival, apoptotic cell death, and innate immune activation, we investigated whether signaling pathways activated in response to specific types of DNA-damaging chemotherapy could enhance subsequent antitumor immune responses,” the investigators explained.
The MIT team began by treating cancer cells with several different chemotherapy drugs, at different doses. Twenty-four hours after the treatment, the researchers added dendritic cells to each dish, followed 24 hours later by T cells. Then, they measured how well the T cells were able to kill the cancer cells. To their surprise, they found that most of the chemotherapy drugs didn’t help very much. And those that did help appeared to work best at low doses that didn’t kill many cells.
The researchers later realized that this was because it wasn’t dead tumor cells that were stimulating the immune system. Instead, the critical factor was cells that were injured by chemotherapy, but were still alive. “… our findings point toward the concept of “immunogenic cell injury” rather than immunogenic cell death, as being critical for promoting antitumor T cell responses after DNA-damaging chemotherapy,” they commented.
“This describes a new concept of immunogenic cell injury rather than immunogenic cell death for cancer treatment,” Yaffe said. “We showed that if you treated tumor cells in a dish, when you injected them back directly into the tumor and gave checkpoint blockade inhibitors, the live, injured cells were the ones that reawaken the immune system.”
The drugs that appear to work best with this approach are drugs that cause DNA damage. The researchers found that when DNA damage occurs in tumor cells, it activates cellular pathways that respond to stress. These pathways send out distress signals that provoke T cells to leap into action and destroy not only those injured cells but any tumor cells nearby.
In studies of mice with melanoma and breast tumors, the researchers showed that the treatment approach eliminated tumors completely in 40% of the the animals. “Administration of ex vivo chemotherapy–treated live injured tumor cells directly into a preexisting tumor in vivo functioned as a potent immune adjuvant when given in combination with systemic ICB in mouse cancer models,” they noted. Furthermore, when the researchers injected cancer cells into these same mice several months later, their T cells recognized them and destroyed them before they could form new tumors.
The researchers also tried injecting DNA-damaging drugs directly into the tumors, instead of treating cells outside the body, but they found this was not effective because the chemotherapy drugs also harmed T cells and other immune cells near the tumor. Also, injecting the injured cells without checkpoint blockade inhibitors had little effect.
“You have to present something that can act as an immunostimulant, but then you also have to release the preexisting block on the immune cells,” Yaffe said. The authors further noted, “Our finding that chemotherapy-induced live injured cells rather than dead cells are the major determinant of DC-mediated T cell antitumor responses is entirely consistent with many of the concepts embodied in the “danger model” of stress-induced immune activation described by Matzinger in the 1990s.”
While Yaffe hopes to test this approach in patients whose tumors have not responded to immunotherapy, further work will be needed first to determine which drugs, and at which doses, would be most beneficial for different types of tumors. The researchers are also further investigating the details of exactly how the injured tumor cells stimulate such a strong T cell response.
“… our results suggest a potential method to translate these findings into clinical use,” the team concluded. “Tumor cells from patient tumor biopsies could be used together with primary patient-derived or allogeneic DCs and CD8+ T cells to screen for the optimal chemotherapeutic compounds and doses that induce an immunogenic cell injury response. These injured cells could then be reinjected into the same tumor in combination with systemic checkpoint blockade.”
The team acknowledged that clinical trials will be needed to test the approach, but maintains that “…this approach has potential for patients whose cancers are accessible for intratumoral delivery and in whom conventional treatment options have failed and initial or acquired resistance to ICB has been observed.”