Sascha Roth remembers the phone call came on a hectic Friday evening.

She was racing around her home in Washington, D.C., to pack for New York, where she was scheduled to undergo weeks of radiation therapy for rectal cancer.

But the phone call from Memorial Sloan Kettering Cancer Center (MSK) medical oncologist Andrea Cercek changed everything, leaving Sascha "stunned and ecstatic - I was so happy."

Dr. Cercek told Sascha, then 38, that her latest tests showed no evidence of cancer, after Sascha had undergone six months of treatment as the first patient in a clinical trial involving immunotherapy at MSK.

Immunotherapy harnesses the body's own immune system as an ally against cancer. The MSK clinical trial was investigating - for the first time ever - if immunotherapy alone could beat rectal cancer that had not spread to other tissues, in a subset of patients whose tumor contain a specific genetic mutation.

100% Remission of Rectal Cancer

These same remarkable results would be repeated for all 14 people - and counting - in the MSK clinical trial for rectal cancer with a particular mutation. While it's a small trial so far, the results are so impressive they were published in The New England Journal of Medicine and featured at the nation's largest gathering of clinical oncologists in June 2022.

In every case, the rectal cancer disappeared after immunotherapy - without the need for the standard treatments of radiation, surgery or chemotherapy - and the cancer has not returned in any of the patients, who have been cancer-free for up to two years.

"It's incredibly rewarding," says Dr. Cercek, "to get these happy tears and happy emails from the patients in this study who finish treatment and realize, 'Oh my God, I get to keep all my normal body functions that I feared I might lose to radiation or surgery.'"

Co-investigator, MSK medical oncologist Luis Diaz, Jr., is equally thrilled. He's spent his career studying how to defeat cancer with immunotherapy. "It's really exciting," says Dr. Diaz, a member of the White House's National Cancer Advisory Board. "I think this is a great step forward for patients."

Using Immunotherapy Earlier

Drs. Cercek and Diaz explain that their team's research was sparked by two key ideas.

The first premise, says Dr. Diaz, is to figure out precisely which patients benefit most from immunotherapy, so they can receive it right away. "Immunotherapy has proven successful in treating a subset of patients with colon and rectal cancer that has metastasized, meaning spread to other tissues."

The patients in this subset, Dr. Diaz explains, have tumors with a specific genetic makeup known as mismatch repair-deficient (MMRd) or microsatellite instability (MSI).

Between 5% and 10% of all rectal cancer patients are thought to have MMRd tumors, including all the patients in the MSK clinical trial that Sascha participated in. There are 45,000 Americans diagnosed a year with rectal cancer.

"An MMRd tumor develops a defect in its ability to repair certain types of mutations that occur in cells. When those mutations accumulate in the tumor, they stimulate the immune system, which attacks the mutation-ridden cancer cells," says Dr. Diaz, who heads the MSK Division of Solid Tumor Oncology and holds the Grayer Family Chair.

But cancer has a trick up its sleeve to stop the immune system from doing its job.

Helping the Immune System

Immune cells contain a safeguard called a checkpoint, to prevent them from attacking normal cells. Cancer cells can trip this safeguard and shut down immune cells, allowing a tumor to hide and grow.

However, immunotherapy can turn the tables yet again.

An immunotherapy agent called a checkpoint inhibitor releases the brake on an immune cell, freeing it to recognize and attack cancer cells.

"When the brakes are taken off the immune cells, MMRd cells look especially strange because they have so many mutations. So the immune cells attack with much more force," explains Dr. Cercek.

Dr. Diaz's pioneering research in treating cancer with immunotherapy had already shown that checkpoint inhibitors could "help people with MMRd colorectal tumors that have spread," he says. "We thought, 'Let's try it before cancer metastasizes as a first line of treatment.' "

Potential Help for Other Cancers

As MSK's rectal cancer trial continues, Dr. Diaz says he hopes "it's the tip of the iceberg." He explains that "we are investigating if this same method may help other cancers where the treatments are often life-altering and tumors can be MMRd. We are currently enrolling patients with gastric (stomach), prostate and pancreatic cancers."

Dr. Diaz has coined a term for this new method of using immunotherapy alone to target MMRd tumors, calling it "immunoablative" therapy - that means using "immunotherapy to replace surgery, chemotherapy and radiation to remove cancer." Dr. Diaz says, "That might sound futuristic - but in this trial, we have a clinical example where that happened."

Today, nearly two years after she began the trial and remains cancer free, Sascha continues to live a normal life. She runs a family-owned home-furnishing and interior design business and often speaks to people facing rectal and other cancers.

"My whole experience has been like a dream," she says. "MSK research and cancer care is simply years and years ahead of where other hospitals - even really good ones - are or should be."