Cracking the cancer code: Can immune therapy treat tumors?

Celine Ryan is proof that T-cell therapy — a medical breakthrough that has transformed the outlook for patients with advanced blood cancers — can be extended to solid tumor cancers.

In July 2015, researchers at the National Cancer Institute used the suburban Detroit woman's own immune system T cells to successfully treat colon cancer that had spread to her lungs. Her solitary case was so exciting that it was published in a prestigious medical journal, and earned a flurry of headlines.

"Every checkup I've had has been 100 percent great," the cancer-free 52-year-old mother of five said in a recent interview. "It feels like a miracle to me."

Still, Ryan is also an ultra-rarity. She is a tantalizing exception to the disappointments that have crushed vast efforts to harness T cells to fight solid malignancies, which account for 90 percent of the 1.7 million new cancers diagnosed annually in the United States.

"There are still many hurdles to successfully applying these therapeutic approaches more broadly to solid tumors," concludes a new paper in the journal Science co-authored by University of Pennsylvania immunotherapy pioneer Carl June.

The senior author, Penn immunotherapy researcher Michael C. Milone, was blunter in an interview: "In solid tumors, we haven't had anything close to success, outside of melanoma."

The paper is the latest to review why solid tumors are defying technology that works well in blood cancers, and how the obstacles might be overcome.

Some background: A T cell, or T lymphocyte, is a type of white blood cell that plays a crucial role in the immune system. T cells scan the intracellular environment and then, with the help of other parts of the defense system, target and destroy invaders such as viruses. The T cells do this by homing in on the germs' distinctive molecular markers, called antigens.

Malignant cells also produce antigens. These antigens may be unique to tumor cells, but usually, cancerous cells have more of the markers than normal cells do. Either way, the immune system tends to be highly tolerant of the abnormalities because tumors arise from the body's own tissues, unlike infections, which are caused by outside invaders.

The goal of T-cell therapy is to override this tolerance. One approach involves removing T cells from the patient's blood, genetically programming them to target a tumor antigen, then returning them to launch an attack.  In solid tumors, provoking a strong, sustained attack has proved to be much harder than it sounds — and much riskier. If T cells target an antigen that turns out to be on healthy as well as tumor cells, the results can be toxic, or even deadly.

"The biggest challenge we currently face is finding safe targets," Milone said.

In certain blood cancers, this problem of collateral toxicity is not so much avoided as managed. The patient's T cells are programmed to attack an antigen on B cells, the white blood cells that turn malignant in many leukemias and lymphomas. The T cells wipe out all of the patient's B cells — normal as well as cancerous — but B cells are dispensable. Their infection-fighting function can be replaced with shots of immunoglobulin, an immune-boosting drug.

About six years ago, June's team at Penn, working with Stephan Grupp's group at Children's Hospital of Philadelphia, were the first to use this approach to achieve spectacular, lasting remissions in terminally ill blood cancer patients. That led to a partnership with Novartis and to last year's approval of the first T-cell therapy, Kymriah, for pediatric leukemia. Months later, Kite's Yescarta was approved for lymphoma; it was originally developed by a National Cancer Institute team led by Steven A. Rosenberg, who treated Ryan.  Many other companies are racing to develop T-cell "living drugs" for blood cancers.

To identify antigens that can be safely targeted in solid tumors, researchers conduct sophisticated preclinical studies, including cell cultures, animal tests, and computer analyses. Occasionally, this still isn't enough.

In 2013, for example, two giants in the field of immunotherapy — Penn's June and the NCI's Rosenberg — each published a report of fatal side effects using T cells engineered to target an antigen called MAGE-A3. The Penn T-cell therapy attacked the hearts of two melanoma patients. The NCI therapy attacked the brains of a patient with melanoma and another with esophageal cancer.

Rosenberg said he is now concentrating on a different T-cell technology, the one that worked in Ryan. Instead of engineering T cells to recognize an antigen, Rosenberg's lab seeks to isolate a rare, powerful subgroup of T cells from each patient's tumor samples.

Called "tumor-infiltrating lymphocytes," or TILs, these elite T cells have a natural ability to recognize the exquisitely complex abnormalities that distinguish tumor cells — and to launch a precise attack. Identifying TILs requires vast DNA sequencing and data crunching, and the cells must be multiplied by the billions before being given back to the patient. So far, dramatic tumor regressions have been achieved in four patients with advanced colon, cervical or liver cancer, Rosenberg said.

"We're working round the clock to develop this treatment that potentially would be applicable to any cancer," Rosenberg said.

Ryan's case was a landmark for another reason. The six lung tumors that her TILs eradicated were driven by a mutation in the KRAS gene, which is involved in sending signals that control cell growth, maturation, and death.  KRAS defects are believed to cause nearly half of colon cancers and almost all pancreatic cancers. Before her, all efforts to develop a therapy that targets mutant KRAS had failed; researchers called it "undruggable."

Yet Ryan's case also shows what a formidable foe science is up against. A seventh lung tumor that her TILs did not shrink had to be surgically removed. An analysis revealed the tumor cells had evolved a new mutation that enabled them to evade the T-cell therapy.

The same problem has been identified in some children whose leukemia returned after successful treatment with the T-cell therapy now called Kymriah.

"I was questioning the guys in [Rosenberg's] lab and my doctors," recalled Ryan, whose professional background includes mechanical engineering. "When I learned how cancer works — what little I could understand – I was just shocked by how resilient it is."