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Pioneer Takes Aim at Solid Tumors With T Cells

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000547229.73538.70

Great men and women of medicine were once impressionable children. Their individual paths were gradually mapped by diverse experiences, directional inspirations, demanding education, and extreme intellectual curiosity.

For Steven A. Rosenberg, MD, PhD, Chief of the Surgery Branch at the NCI, one of history's darkest periods guided him toward a monumental career enveloping medical “firsts” that continue to shape the emerging potential of adoptive cell therapies (ACT) and the aggregate field of oncology.

“My parents were born in Poland and came here to escape persecution,” said Rosenberg speaking by phone from his Bethesda, Md., office. “I was born in 1940. When I was 5 or 6 years old, virtually all of my parents' families were wiped out in the Holocaust. I remember seeing postcards arriving in the mail saying this relative died at Auschwitz, and that relative died at Buchenwald. It was a horrible experience. I learned that people could be evil; I wanted to be the opposite. Oh sure, I originally wanted to be a cowboy. But by 6 years of age, I converted to medicine.”

That conversion eventually resulted in Rosenberg earning a PhD in biophysics, graduating from medical school, and embracing an early belief in the power of the immune system to impact—and possibly cure—cancer. While working on a surgical residency at Harvard, Rosenberg observed what he calls “one of the rarest events in all of medicine. I saw a patient who, in the absence of treatment, had a spontaneous regression of cancer. There was no good explanation for it. It seemed to be something within the body's protective mechanism that was able to accomplish that, and it made me think about use of the immune system. It sparked my interest.”

That interest has never waned. In earlier days, he treated patient after patient for whom traditional treatments had failed, trying to stimulate their immune responses to cancer cells invading their bodies. It was not until he treated the 67th such patient in 1984 that his efforts bore fruit. Patient 67 was a young woman with widespread metastatic melanoma. Rosenberg and colleagues treated her with an immune stimulant, interleukin-2 (IL-2), a hormone with no impact on cancer cells, but striking impact on the immune system. The patient's cancer disappeared (New Engl J Med 1985;313:1485-1492). To this day, Patient 67 is alive and well and living in Florida.

Last year, she and Rosenberg were featured on a Discovery channel documentary, “First in Human.” “She was the first patient ever to respond to an immunotherapy and have her cancer disappear,” said Rosenberg. And in 1992, IL-2 became the first immunotherapy ever approved by the FDA. In light of those achievements alone, one might rightly confer upon Rosenberg the title of “pioneer” in immunocellular therapy.

But he has continued the arduous work and, through the decades, Rosenberg and team have developed, tested, and trialed several different forms of ACT and reported promising findings in patients with varying advanced cancers. He has been instrumental in the development of chimeric antigen receptor (CAR) T-cell therapy, which is already having tremendous impact on hematologic cancers (a topic explored in September's inaugural issue of Hem Onc Times).

But unlike some researchers working specifically in the CAR T-cell space who expect the therapy to make a leap to solid tumors, Rosenberg believes the best hope for a cure for solid tumors will be found in the potential of naturally occurring T cells (as opposed to the genetically re-engineered CARs).

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The Potential of T Cells

“From an oncologic standpoint, I think that the best approach that we have right now for developing effective treatments for solid cancers that kill almost 600,000 Americans in a single year is to figure out ways to stimulate the immune system against the unique cancer mutations in each patient. That represents the most exciting area for future development,” Rosenberg stressed.

It is very much the direction that work in his lab is taking. “Once we saw that stimulating the immune system with IL-2 could cause a complete regression of cancer, it became clear there must be T cells in that patient that caused the regression,” recounted Rosenberg. That watershed moment led to a series of studies showing that by isolating tumor-infiltrating lymphocytes, multiplying them ex vivo, and delivering them back to the patient, tumor regression in metastatic cancer can be mediated, as evidenced by Rosenberg's continuing clinical observations of cancer regressions.

“After a great deal of additional work, we published a paper [Nature Med 2013;19:747-742] in which we showed that these cells were actually recognizing the unique mutations that were present in the cancer. This is a very important and deep insight,” he stressed. “The immune system is attacking cancers by recognizing the very products of the DNA mutations that cause the cancer.”

Rosenberg noted that common cancers that cannot be impacted by any current treatment and generally impervious to checkpoint modulators, CAR T cells, etc., “... start in the epithelial lining of organs, the cells that are turning over constantly. We are talking about the rectum, colon, esophagus, stomach, ovaries, prostate, pancreas, liver, etc. All of those kinds of cancers form because a normal cell mutates as those cells divide. And when you accumulate enough mutations it becomes a cancer cell. What we described for the first time in 2013 in Nature Medicine is the fact that these cell transfer immunotherapies work by targeting the products of these very DNA mutations that caused the cancer.”

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Beyond Melanoma

Rosenberg's work has expanded from that landmark regression of melanoma, in Patient 67, to achieving regression of advanced liver cancer in a patient who had been refractory to chemotherapies and other treatments. “The patient has had a regression, now lasting almost 5 years,” he noted. The work was detailed in two papers (Science 2014;344:641-645; Science 2015;350:1387-1390).

The continuing research also prompted an important paper on the final common pathway of all immunotherapies (Nature Immunol 2017;18:255-262). “We now realize that all the immunotherapies—the checkpoint modulators, all of the natural immunotherapies—are likely targeting the very mutations that cause the cancers in the first place. It is quite ironic that the mutations that cause the cancer are going to be the Achilles heel of treating that cancer.”

Although Rosenberg has been instrumental in the remarkable gains in using CAR T-cell therapy with hematologic cancers, he is quick to assert, “There is one very important point: there are no examples of CAR T cells being able to successfully treat a patient with a solid tumor. CAR T cells, which depend on antibody recognition, have thus far had no application at all in the treatment of common solid cancers.

“The problem with CAR T cells is, in order for them to attack, there must be an antibody that recognizes a cell surface determinant. But there are no such monoclonal antibodies that are unique to solid cancers and are not found on normal cells. When you try to target something that is on normal cells, you also kill those normal cells. There have been disasters in the development of this whole form of cell transfer therapy that have resulted in deaths because normal cells were attacked. This is why our new approach is so exciting. We are attacking the mutations unique to each patient's cancer and the normal cells are completely unaffected.”

In addition to using T cells to cure people with liver tumors, Rosenberg and team also treated a patient with breast cancer who had been through seven different chemotherapy regimens, hormonal regimens, and targeted therapies.

“There was a tumor growing out of her chest wall, multiple liver metastases; probably a third of her liver was replaced by cancer,” he described. “There were no treatments left for her. We gave her cell therapy targeting her own unique mutations and everything disappeared. Now her cancer is in complete regression [Nature Med 2018;24(6):724-730]. We've also treated cervical cancer and colon cancer using conventional T cells [New Engl J Med 2016;375:2255-2262].”

Rosenberg said he and fellow researchers are ramping up their work with T cells.

“We are working round the clock right now because we feel we finally have a blueprint for success. I now believe it is the normal T cells' recognition of these mutations in the cancer that result in cancer regression. Just as some detractors wrongly believed CAR T cells were too complicated to work, they now doubt the potential of naturally occurring T cells. Cells that can recognize cancer mutations are exceedingly rare—anywhere from one in a thousand to one in a million. But now we can identify those cells, not only in the tumor, but sometimes circulating in the peripheral blood,” he explained.

“They don't need to be re-engineered. We isolate them and grow them. Additionally, we are trying to make them even more powerful by isolating the receptors from the natural anti-tumor T cells and putting them into a patient's peripheral cells the way we do with CAR T cells. Then we can get up to 90 percent of the cells expressing the same receptor able to target the solid cancer. I am very excited about that.”

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Essential Components to Progress

Rosenberg said he has likely trained about 400 fellows in labs over the last 40 years. And they often have posed the same question: “What does it takes to make progress in research?”

“I tell them if you really want to make progress it takes two essential components. The first is an over-used word—passion. But what I mean by that is you have to be passionate enough about your work that you commit to it completely, immersing yourself in the problem you are trying to solve. When you are waiting for a red light to change, when you are taking a shower, when you are alone, that is what your mind is thinking of. You have to be so deep into your work that you gain true understanding of what the real biologic issues are.

“The second essential component is you need a laser focus on your goal. Some people define basic research as shooting an arrow into the air and painting the target wherever it lands. But this is not pure basic research. This is an attempt to use modern science to help people, and if you keep that goal in mind, with laser sharpness, you can make progress.”

Asked what he hopes to achieve before retiring, Rosenberg answered without hesitation. “You know I always have a dozen patients at any one time, and all of them are dying of cancer. That helps me keep my perspective. I want to be able to cure patients with solid cancers. I've been doing this a long time, but right now I finally feel like I am getting the hang of it.”

Valerie Neff Newitt is a contributing writer.

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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