August 30, 2017 was a momentous day for cancer immunotherapy researchers at Penn's Abramson Cancer Center and around the world. In a historic decision, the Food and Drug Administration (FDA) approved the first cellular therapy for cancer: tisagenlecleucel (Kymriah®) for pediatric acute lymphoblastic leukemia (ALL). 

Within eight months, FDA approval was expanded to include adult diffuse large B-cell non-Hodgkin lymphoma (NHL). Stephen J. Schuster, MD led two key studies in NHL. One included 27 sites in 10 countries across North America, Europe, Australia, and Asia. 

Kymriah® works by reengineering a person’s own T cells to fight cancer. It’s unique in that it is a living drug. Years beyond treatment, patients retain powerful T cells in their bodies. The drug was developed at Penn by Carl H. June, MD in collaboration with Novartis Pharmaceuticals. 

Pediatric researcher Stephan A. Grupp, MD, PhD provided critical testimony to the FDA on behalf of CAR T. He has worked closely with Drs. Carl June, Bruce Levine, and David Porter to make T-cell therapy a reality since first meeting Dr. June in 2000.

Dr. Grupp led the first global registration trial for CAR T-cell therapy, which in turn led to FDA approval. He also oversaw the treatment of the first child treated with CAR T-cell therapy, Emily Whitehead. Now six years cancer-free, Emily Whitehead is a typical 13-year-old who loves animals, school, spending time with friends, and late night slumber parties.

Turning Cancer Fears into Cancer Fierce

The FDA maintains a rigorous review process for all drug approvals. The process is more so for a completely new kind of drug.

Dr. Grupp recalls the pressure, “This testimony defined a new field of medicine. There were many issues that had to be settled because it was a new kind of product. We had to answer the questions in a way that would be useful in the future and help get this therapy to more patients.”

Dr. Grupp leads the cancer immunotherapy program at Children’s Hospital of Philadelphia (CHOP). CHOP has treated over 250 children with CAR T since 2012, more cell therapy patients than any other institution.

Moving forward, Penn and CHOP plan to capitalize on the connection between today’s cellular therapies and bone marrow transplant (BMT). Both of our institutions have established cell therapy and transplantation programs under the direction of Drs. Porter (Penn) and Grupp (CHOP), respectively. 

Our program creates an umbrella, linking the existing BMT and cellular therapy groups.

“There is a lot of synergy in combining these disciplines. We can take advantage of the expertise gained over the years in BMT, cell collection, cell manipulation, and clinical care and combine it with expertise in pioneering cell therapies,” says Dr. Porter.

On a Course to Cure

Accelerating the Immunorevolution 

“We know that the platform is effective. The question is how can we make it work better.” Penn’s Saar I. Gill, MD, PhD, discusses the future of CAR T-cell therapy research. Dr. Gill is one of many scientists spurring the ImmunoRevolution at Penn’s Abramson Cancer Center. 

Last year’s landmark FDA approval of T-cell therapy drugs to treat specific kinds of leukemia and lymphoma opened the door to new avenues of cancer immunotherapy research. 

Dr. Gill describes the rationale behind one of his studies that combines a targeted therapy with T-cell therapy in people with chronic lymphocytic leukemia: “If you can decrease the disease burden, you can come in with CAR T cells at a time when the patient is feeling well, has less disease, and therefore is likely to respond better and have fewer side effects.” 

Dr. Gill was drawn to immunotherapy early in his training: “At every step of the way, I was very interested in how we could recruit the power of the immune system to do more than it is doing now.” 

Immunotherapy extends beyond T-cell therapies to include vaccines, checkpoint inhibitors, and monoclonal antibodies. The field is wide open for young researchers and students, many of whom gravitate to Penn because of the accomplishments of Dr. June and others. 

New Partners

The National Cancer Institute recently awarded Drs. June, Gill, and colleagues a prestigious multi-investigator program project grant to continue studies of T-cell therapy. Penn also benefits from many generous donors and partnerships with other institutions through efforts such as Stand Up to Cancer. Penn was one of six founding members of the Parker Institute for Cancer Immunotherapy, a national network of leaders in cancer immunotherapy research. 

Dr. June notes the advantages of working with other institutions: “We can be much more nimble with novel cancer therapies and especially immunotherapies. It allows us to leverage the individual expertise of other cancer centers. Patients benefit because trials get opened more rapidly. Instead of competing science, it’s collaborative science.”

Collaborative Science Leads to Cancer Cures

Some of the approaches under study include: 

Combination Therapies

Scientists study new ways to combine immunotherapy with targeted therapy, chemotherapy, other forms of immunotherapy, and even radiation therapy. For example, the RadVax team, led by Robert H. Vonderheide, MD, DPhil, Director of the Abramson Cancer Center, and radiation oncologist Andy J. Minn, MD, PhD, is exploring the use of immunotherapy to improve response to radiation. 

This study builds on research started in melanoma in 2015 and involves Amit Maity, MD, PhD and E. John Wherry, PhD. They recently received a large program project grant from the National Cancer Institute to support this work, which includes clinical trials in multiple tumor types and translational studies. 

Gene Editing 

A new trial tests the use of CRISPR gene editing technology and T-cell therapy to treat multiple myeloma, sarcoma, and melanoma. Penn leads this first Parker-funded clinical trial. 

Edward A. Stadtmauer, MD, directs the effort — in collaboration with Kristy M. Weber, MD and Lynn L. Schuchter, MD — and a host of early-career cancer researchers focused on understanding and leveraging CRISPR technology.

Another line of research, led by Dr. Gill, uses CRISPR to modify normal cells to treat acute myeloid leukemia (AML). Explains Dr. Gill, “You can do one of two things. You can make cancer cells express a target normal cells do not, or you can take away the shared target from normal cells and only leave it on the cancer cells. We’ve developed a technology to do the latter in AML.” 

His colleague, Marco Ruella, MD, screens drugs and gene knockouts using a CRISPR approach to discover new ways to enhance CAR T-cell attack of cancer. 

Further CAR T-Cell Therapy Research

Continuing research by Dr. June’s lab and others focuses on improving CAR technology and combining it with other forms of treatment. Studies address: 

• Understanding why T-cell therapies do not work for some patients
• Combining T-cell therapies in dualCAR trials, like one Dr. Stadtmauer is conducting for patients with multiple myeloma
• Moving beyond CD19 (the Kymriah® target) to find new CAR targets, such as CD22. (CD22 is found in 90 percent of acute lymphocytic leukemia cells and is the focus of study of Noelle Frey, MD, MSCE and pediatric researchers Stephan Grupp, MD, PhD and Shannon L. Maude, MD, PhD.)