A boost for cancer immunotherapy

June 01, 2020

CAMBRIDGE, MA -- One promising strategy to treat cancer is stimulating the body's own immune system to attack tumors. However, tumors are very good at suppressing the immune system, so these types of treatments don't work for all patients.

MIT engineers have now come up with a way to boost the effectiveness of one type of cancer immunotherapy. They showed that if they treated mice with existing drugs called checkpoint inhibitors, along with new nanoparticles that further stimulate the immune system, the therapy became more powerful than checkpoint inhibitors given alone. This approach could allow cancer immunotherapy to benefit a greater percentage of patients, the researchers say.

"These therapies work really well in a small portion of patients, and in other patients they don't work at all. It's not entirely understood at this point why that discrepancy exists," says Colin Buss PhD '20, the lead author of the new study.

The MIT team devised a way to package and deliver small pieces of DNA that crank up the immune response to tumors, creating a synergistic effect that makes the checkpoint inhibitors more effective. In studies in mice, they showed that the dual treatment halted tumor growth, and in some cases, also stopped the growth of tumors elsewhere in the body.

Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, and a member of MIT's Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science, is the senior author of the paper, which appears this week in the Proceedings of the National Academy of Sciences.

Removing the brakes

The human immune system is tuned to recognize and destroy abnormal cells such as cancer cells. However, many tumors secrete molecules that suppress the immune system in the environment surrounding the tumor, rendering the T cell attack useless.

The idea behind checkpoint inhibitors is that they can remove this "brake" on the immune system and restore T cells' ability to attack tumors. Several of these inhibitors, which target checkpoint proteins such as CTLA-4, PD-1, and PD-L1, have been approved to treat a variety of cancers. These drugs work by turning off checkpoint proteins that prevent T cells from being activated.

"They work incredibly well in some patients, and they've given what some would call cures, for about 15 to 20 percent of patients with particular cancers," Bhatia says. "However, there's still a lot more to do to open up the possibility of using this approach for more patients."

Some studies have found that combining checkpoint inhibitors with radiation therapy can make them more effective. Another approach that researchers have tried is combining them with immunostimulatory drugs. One such class of drugs is oligonucleotides -- specific sequences of DNA or RNA that the immune system recognizes as foreign.

However, clinical trials of these immunostimulatory drugs have not been successful, and one possible reason is that the drugs are not reaching their intended targets. The MIT team set out to find a way to achieve more targeted delivery of these immunostimulatory drugs, allowing them to accumulate at tumor sites.

To do that, they packaged oligonucleotides into tumor-penetrating peptides that they had previously developed for delivering RNA to silence cancerous genes. These peptides can interact with proteins found on the surfaces of cancer cells, helping them to specifically target tumors. The peptides also include positively charged segments that help them penetrate cell membranes once they reach the tumor.

The oligonucleotides that Bhatia and Buss decided to use for this study contain a specific DNA sequence that often occurs in bacteria but not in human cells, so that the human immune system can recognize it and respond. These oligonucleotides specifically activate immune cell receptors called toll-like receptors, which detect microbial invaders.

"These receptors evolved to allow cells to recognize the presence of pathogens like bacteria," Buss says. "That tells the immune system that there's something dangerous here: Turn on and kill it."

A synergistic effect

After creating their nanoparticles, the researchers tested them in several different mouse models of cancer. They tested the oligonucleotide nanoparticles on their own, the checkpoint inhibitors on their own, and the two treatments together. The two treatments together produced the best results, by far.

"When we combined the particles with the checkpoint inhibitor antibody, we saw a vastly improved response relative to either the particles alone or the checkpoint inhibitor alone," Buss says. "When we treat these mice with particles and the checkpoint inhibitor, we can stop their cancer from progressing."

The researchers also wondered whether they could stimulate the immune system to target tumors that had already spread through the body. To explore that possibility, they implanted mice with two tumors, one on each side of the body. They gave the mice the checkpoint inhibitor treatment throughout the entire body but injected the nanoparticles into only one tumor. They found that once T cells had been activated by the treatment combination, they could also attack the second tumor.

"We saw some signs that you could stimulate in one location and then get a systemic response, which was encouraging," Bhatia says.

The researchers now plan to perform safety testing of the particles, in hopes of further developing them to treat patients whose tumors don't respond to checkpoint inhibitor drugs on their own. To that end, they are working with Errki Ruoslahti of the Sanford Burnham Prebys Medical Discovery Institute, who originally discovered the tumor-penetrating peptides. A company that Ruoslahti founded has already taken other versions of the tumor-penetrating peptides into human clinical trials to treat pancreatic cancer.

"That makes us optimistic about the potential to scale up, manufacture them, and advance them to help patients," Bhatia says.
-end-
The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, a Core Center Grant from the National Institute of Environmental Health Sciences, and the Koch Institute's Marble Center for Cancer Nanomedicine. Bhatia also has affiliations with the Ludwig Institute for Cancer Research, the Broad Institute of MIT and Harvard, the Wyss Institute for Biologically Inspired Engineering, the Howard Hughes Medical Institute, and Brigham and Women's Hospital.

Massachusetts Institute of Technology

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.