In 2013, Science Magazine named cancer immunotherapy the "Breakthrough of the Year." The article explored various types of cancer immunotherapy, including chimeric antigen receptor therapy, known as CAR-T, and pointed out that these therapies have been a long time in the making, with clinical trials going back thirty-plus years.
CAR-T may be a 2015 buzzword, but, "LLS has been supporting this work for nearly two decades with a commitment of $21 million," explained Louis J. DeGennaro, President and CEO of The Leukemia and Lymphoma Society (LLS), in an interview with BioPharma Dive about the evolving role of immunotherapy in blood cancer treatment.
The science behind CAR-T
CAR-T is a therapy in which T-cells are removed from a patient’s body and re-engineered to make them into deadly cancer-seeking cells, which then target a particular cancer and destroy it. On a molecular level, CARs are proteins that are attached to the T-cell during the modification process. They reenter the body looking for their match—specifically the antigens (also proteins) on tumor cells. The intention is to create an intense attraction, followed by a swift demise.
CAR-T has become such a talked-about therapy that many people might assume that it’s commercially available. In fact, CAR-T has not been approved for clinical use by any regulatory agency, but oncology researchers are hard at work attempting to take early-stage studies and turn them into viable, reproducible clinical therapies.
Novartis and U Penn team up
Much of the earliest and most ground-breaking work has occurred at the University of Pennsylvania, where researchers have been using Novartis’s CAR treatment-in-development, CTL019, to treat children with leukemia and lymphoma at the Children’s Hospital of Philadelphia (CHOP). In this case, the target protein on the blood cancer cells is CD19.
For the U. Penn researchers, led by Carl H. June, MD, the focus of their research has been treating children with relapsed acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). ALL is the most common cancer diagnosed in children, representing about 25% of all cancer diagnosed in people aged 15 or younger. In children, ALL remission rates are generally high during the first round of treatment, hovering at the 90% mark; however, if the disease reoccurs, success rates are significantly lower and treatment options are limited.
The goal of researchers at CHOP and other child-focused cancer treatment centers is to develop a CAR-T option that can extend the lives of these patients—and in fact allow them to have a normal lifespan.
Success and challenges in phase I/II
Last year, the U. Penn researchers presented data to their peers highlighting early successes. In a study of 39 children with ALL treated with CTL019, 92% experienced complete remission, with 70% of the responders still in remission six months later and 75% of patients still alive. They also presented data on the effect of CTL019 on response rates in children with chronic lymphocytic leukemia (CLL) and follicular lymphoma. For example, in a phase II study of 24 patients with CLL, treatment with CTL019 elicited a 42% response rate. In the same study, 36% of patients were cancer free three months later. This generated considerable excitement, considering the fact that the 10-year survival rate for CLL is less than 35%.
Researchers are planning more phase II trials, and starting to design phase III studies; however, there has been a major problem in trials. Cytokine release syndrome (CRS), an extreme inflammatory response to CAR-T, leads to flu-like symptoms and can be fatal. In fact, three patients died from CRS in Novartis trials. A key part of developing CTL019 has been investigating ways to manage CRS without compromising treatment goals—a major clinical challenge, because the occurrence of CRS is often correlated with a high disease burden. The good news is that research in this area is growing every day, with numerous published reports that will eventually become the basis for treatment guidelines.
Novartis and U. Penn are definitely CAR-T pioneers, with a focus on blood cancers, but they are in good company. The list of companies involved in CAR-T also includes Amgen, Kite Pharma, Intrexon, Merck Serono, Ziopharm, Cellectis, Bluebird and Pfizer. In many cases, smaller biotech companies are aligned with larger companies, who are able to fund development of CAR-T, while leveraging the focus and technical platforms of the smaller biotechs.
There are literally hundreds of millions of dollars being invested in CAR-T via various funding mechanisms and partnerships. Within the last month alone, Merck Serono and Intrexon struck a $941 million CAR-T co-development deal, while Cellectis, which is partnered with Pfizer, filed for a $197 million IPO.
The pioneering role of blood cancer research
CAR-T is available through clinical trials. It is not yet mainstream, but researchers are determined to make it part of the treatment paradigm. Based on the pace of blood cancer research, the chances are good that the first approvals for CAR-T will be in this area. Like many other life-changing therapies, CAR-T is a metaphorical concept involving targets, attraction, receptors, death and ultimately, life. The outlook is good—especially for blood cancers.
DeGennaro, who is as pragmatic as he is optimistic, says, “As we gain greater understanding of the molecular underpinnings of blood cancers and are able to develop more precise therapies to target the genetic aberrations that drive the cancer, I believe we will see vastly improved survival rates in the future."