Chimeric Antigen Receptor Pioneer Sees Solid Tumor Potential

Carl H. June, MD

Regarded as a revolutionary advance in combating various hematologic malignancies, chimeric antigen receptor (CAR) gene transfer therapy has exhibited such promise as an anticancer strategy that the approach is likely to be explored across a broad range of solid tumors, according to Carl H. June, MD.

June, who is widely known as a pioneer of this groundbreaking therapy, anticipates that the novel class of agents will improve as research continues, and that the therapies may eventually have wide applications.

“It will be kind of like computer systems, where we are just seeing the launch of Windows 10. What we have right now is CAR 1.0, and I think these therapies are going to get better with the next generations,” June said in an interview with OncologyLive.

“The big question in the field really surrounds solid cancers,” said June. “For example, what will the role of this kind of immunotherapy be with lung cancer? Trials will begin in every solid cancer you can think of by various groups over the next year or so.”

June is the Richard W. Vague Professor in Immunotherapy at the Perelman School of Medicine and director of Translational Research in the Abramson Cancer Center at the University of Pennsylvania. In May, he was honored with the 2015 Giants of Cancer Care award in the Immuno-Oncology category.

June is the leading investigator into CTL019, the world’s first successful and sustained demonstration of the CAR gene transfer therapy as a treatment for patients with leukemia. CTL019 is a form of adoptive immunotherapy in which autologous T-cells are engineered through lentiviral transduction to express a CD19-specific CAR. The autologous T cells are collected through leukapheresis, modified, and then activated ex vivo using anti-CD3/CD28 beads.

In clinical studies, the therapy has demonstrated overall response rates of 90% in adults and children with acute lymphoblastic leukemia (ALL),¹ 47% in patients with chronic lymphocytic leukemia,^2,3 and 68% in individuals with CD19-positive non-Hodgkin lymphomas including diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma.⁴ The agent also has shown promise in multiple myeloma.⁵

In July 2014, the FDA granted CTL019 a breakthrough therapy designation as a possible treatment for pediatric and adults patients with relapsed/refractory ALL.

In addition to CTL019, researchers at the University of Pennsylvania are developing CART-meso, in which autologous T cells are modified to target tumor cells expressing the mesothelin protein in patients with advanced solid tumors.⁶ A pilot study also is ongoing in metastatic pancreatic cancer.⁷

June shared his thoughts on the evolution and impact of CTL019 and the potential of CAR therapies in an interview with OncologyLive.

OncologyLive: We understand that you have exciting news to share regarding the 5-year survival rate of one of your patients. Can you discuss this?

Dr June: We have worked on making these CAR T cells for about 25 years. However, it was not until July 31, 2010, that our first patient was treated. Now, he has just passed the 5-year landmark and remains free of leukemia, which was his initial form of cancer, and he is enjoying his retirement.

Please describe the therapeutic process using chimeric antigen receptor therapy.

What we do, really, is an ultimate form of personalized medicine. In this case, it starts with a patient’s own immune system. The white blood cells are taken out from the patient’s arm and, in that 5 to 10 day manufacturing process, those cells are then engineered to become leukemia-specific killers, although we can now make them toward other kinds of cancers.

Then, they are given back as a simple blood transfusion to the patient. It is different from all previous therapies in that these are gene-modified. This gene transfer technology makes the cells chimeric. Therefore, they have the properties of other cells but they are not found naturally in the body, so this synthetic biology makes the immune system better than it was to start.

The second unique property is that these cells are living drugs. Our first patient that we mentioned had his infusion 5 years ago, and we still detect these cells in his body. They are hunter cells that are on patrol, and that is the power of the immune system. It can have a memory—in this case, cells that are anti-leukemic maintain the memory—and they have prevented the tumor from coming back.

Could this therapy have an impact in other B-cell and nonhematologic malignancies?

Worldwide, there are large groups of people, labs, and both companies and universities available to develop this into other kinds of therapies. Our initial treatment, 5 years ago, was for chronic lymphocytic leukemia. There are about 15,000 new patients in the United States each year diagnosed with that, and it is not curable with any of the standard therapies.

In 2012, we began treating acute leukemia for both adults and children, and we have received that as a breakthrough designation status from the FDA last summer; Novartis is conducting multicenter international trials for that. They expect to apply to the FDA next year for approval.

Now, we are treating various kinds of lymphomas; these studies are ongoing and have been very successful so far. We have even treated some patients with myeloma. We have had very encouraging results there. I think in every kind of bone marrow cancer, there are trials either just beginning or will begin within the next year to extend this out beyond the B-cell leukemias where we started 5 years ago.

The big question in the field really surrounds solid cancers. For example, what will the role of this kind of immunotherapy be with lung cancer? Trials will begin in every solid cancer you can think of by various groups over the next year or so.

Do you envision these CAR therapies being administered in the community and/or even nonacademic settings, or will it remain in more specialized environments?

We have strong evidence that suggests that, in very late-stage leukemias, approximately one-third of patients need to be in intensive care environments that are found in cancer centers.

However, we have found that as you move this earlier on in patients, where they do not have such advanced disease and high levels of cancer, that it can be done in a community hospital setting. Over a period of years, people will learn how to do that. It is initially starting in advanced cancer centers, and then can later be done in community hospitals.

Right now, when patients are diagnosed with leukemia, the first therapy is chemotherapy and/or radiation therapy. What we would like to have that be is a targeted immunotherapy and replace the need for chemotherapy.

Some patients have died from cytokine release syndrome on previous studies with CAR therapies. What precautions, if any, can be taken to prevent this from happening?

We have learned how to manage this so that, out of about 180 patients, we only had less than five patents actually die from the side effects. That is much less than bone marrow transplantation, for instance. This procedure will eventually rethink, or replace, the need for bone marrow transplantation.

When I began training in bone marrow transplantation in the early 1980s, we had what was called a “rule of 10.” For each decade of life, you had a 10% chance of dying. Therefore, if you were a 30 year old and were undergoing a bone marrow transplant, you had a 30% chance of dying. What we have already is a much lesser risk than it was in the early days of bone marrow transplantation. With time, bone marrow transplantation has gotten much safer. The same thing will happen with CAR T-cell therapy.

The other aspect regarding this is that we have found that if the patients are not in such advanced disease when they are treated, they have virtually no risk of cytokine release syndrome. By treating patients earlier, it will both be done in the community setting and will be an outpatient therapy. Therefore, it is only in the very late-stage patients where about one-third of them need to have advanced care in an intensive environment where that chance is higher.

What have you learned about the immune system and cancer through your CAR research that may be applied more broadly in the field?

We have learned that T cells can be so-called serial killer cells. We have found that each of these gene-modified CAR T cells that we put into patients can be responsible for killing more than 1000 tumor cells; therefore, there is no precedent for where the cells are both living drugs and they divide in the body. The body actually becomes a bioreactor and now we have found that this is possible to do routinely.

Moreover, we have found that there have been no side effects from modifying the T cells. Initially, there was a concern that this could cause a form of T-cell cancer, which would be another form of leukemia. We now have over 1000 patient-years where patients have had these gene-modified cells and not one side effect from that.

It appears safe, and that means there are many, many different kinds of iterations. It will be kind of like computer systems, where we are just seeing the launch of Windows 10. What we have right now is CAR 1.0, and I think these therapies are going to get better with the next generations. I’m very excited about the prospect that they will be safer and more potent with what is going to come down from new research.

Is there anything else regarding CAR T-cell therapies you wish to share?

It is important for scientists to talk, and for the public to now learn, about these new kinds of therapies. Even most physicians have little understanding about how the immune system really works. This is true, especially in the field of oncology, where there was no immunotherapy for cancer until recently. Now, it is a time of education and it is really important to ensure there are no barriers going forward. Education needs to be used in a way that the most benefit will happen for the patient.

References

1. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.
2. Porter DL, Kalos M, Frey NV, et al. Randomized, Phase II dose optimization study of chimeric antigen receptor modified t cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. Blood. 2013;122(21; abstr 873).
3. Porter DL, Kalos M, Frey NV, et al. Chimeric antigen receptor modified t cells directed against CD19 (CTL019 cells) have long-term persistence and induce durable responses in relapsed, refractory CLL. Blood. 2013;122(21; abstr 4162).
4. Schuster SJ, Svoboda J, Nasta SD, et al. Phase II trial of chimeric antigen receptor modified T cells directed against CD19 in relapsed/refractory diffuse large B cell, follicular, and mantle cell lymphomas. Presented at: 13th International Conference on Malignant Lymphoma; June 16-20, 2015; Lugano, Switzerland. Abstract 139.
5. Garfall AL, Maus MV, Lacey SF, et al. Safety and efficacy of anti-CD19 chimeric antigen receptor (CAR)-modified autologous T cells (CTL019) in advanced multiple myeloma. J Clin Oncol. 2015;33 (suppl; abstr 8517).
6. Tanyi JL, Haas AR, Beatty GL, et al. Safety and feasibility of chimeric antigen receptor modified T cells directed against mesothelin (CART-meso) in patients with mesothelin expressing cancers. Presented at: 2015 American Association for Cancer Research Annual Meeting; April 18-22, 2015; Philadelphia, PA. Abstract CT105.
7. NIH Clinical Trials Registry. www.ClinicalTrials.gov website. Identifier: NCT02465983.