There’s a long history of work in cancer immunotherapy, and much of it stems from the early pioneering days of Dr. Steven Rosenberg at the National Cancer Institute (NCI) in the 1980s. Dr. Rosenberg is credited with developing the first immunotherapy regimen using a procedure called adoptive cell transfer, or ACT, for the treatment of patients with melanoma.
The building blocks of ACT are the patient’s own T-cells. These are white blood cells that are essential to the body’s immune response to foreign agents, such as abnormalities and/or infections. In ACT, T-cells are collected from a patient’s tumor samples and brought into a laboratory. The cells with the greatest anti-tumor activity can then be identified and cultured. The newly grown cells, along with a natural cytokine called interleukin-2 (IL-2), are then put back into the patient. This creates an army of cancer killers that attacks the tumors in a way the immune system could not have done by itself.
Since that time, the way T-cells have been used to fight cancer has advanced, and scientists are now able to genetically engineer them to produce specialized receptors called chimeric antigen receptors. These proteins, knowns as CARs, allow the T-cells to seek out and kill cells expressing a particular tumor antigen. It is these cancer assassins that drew the attention of Kite Pharma, a clinical-stage biopharma company focused on the development and commercialization of novel cancer immunotherapy products.
Clinical Success Demonstrates CAR T-Cell Potential
The first clinical trial using CAR T-cells was conducted in 1996 by Dr. Rosenberg and a team of experts. Unfortunately, this and other early studies showed only limited efficacy. However, several factors, including improvements in molecular biology and the understanding of immunology, have generated compelling results in more recent clinical trials. Patients who once had no options for treatment are experiencing stunning results, including many who have gone into complete remission even years after receiving the therapy.
Kite’s chairman, president, and chief executive officer, Dr. Arie Belldegrun, was already very familiar with Dr. Rosenberg’s work, as he was one of the fellows in Dr. Rosenberg’s lab during the development of ACT. As the CAR field evolved, Kite and NCI began exploring a potential collaboration, and in 2012, they entered into a cooperative research and development agreement (CRADA). The goal of this agreement is to bring CAR T-cell therapy forward into clinical development and eventually commercialization.
Dr. Marc Better, VP of product sciences at Kite Pharma, says clinical trials being run at the NIH under the program with Kite are seeing response rates up to and over 70 percent in different groups of patients. “An overall response rate that high in this patient population is almost unprecedented,” notes Dr. Better. Kite’s lead product candidate, an anti-CD19 CAR, will be evaluated in clinical trials for refractory B-cell malignancies (lymphoma and leukemia). These are patients who have failed all other previous treatments. According to a report from the Journal of Clinical Oncology, “out of the 15 patients included in the trial to date, eight showed complete remission, four achieved partial remissions, and one had stable lymphoma (two were not evaluable for response).” It is because of results such as this that the interest in this market has grown tremendously.
In a presentation scheduled at this year’s Cell Therapy Bioprocessing & Commercialization Conference, Dr. Better plans to review clinical information for these products. For the meeting, however, his focus will be on the challenges and opportunities related to the chemistry manufacturing and controls (CMC) associated with bringing them to market.
Off The Beaten Path
As with any autologous cell therapy product, bringing CAR T-cell therapies to market does not come without challenges. The complexity and sensitivity of cell therapy creates a unique set of circumstances that will require the brightest minds in industry to think outside the box for solutions. “Because the modified T-cells are such precision killers, they’re exquisitely sensitive,” he explains. “This is a new class of therapeutic products, and that’s going to create a lot of opportunities for us to learn and to work with the scientific community and the FDA, in order to bring these forward. Like any pharmaceutical product, they have to be consistent, safe, and well-characterized. It’s important everybody is confident that we’re delivering safe and effective medicines to patients that are going to have a lasting clinical benefit.”
There are several groups working on molecules that are similar to the engineered T-cells that Kite and NCI are working on, including academic centers and other companies, both big and small. In July of this year, Novartis, along with the University of Pennsylvania’s Perelman School of Medicine, announced that the FDA had granted Breakthrough Therapy Designation status to its product, CTL019. This investigational CAR T-cell therapy is the result of an exclusive global agreement between Novartis and Penn Medicine, which are striving for the same goal as Kite and the NCI. “There are so many people who see the promise of these types of drugs and want to help bring them into the marketplace,” says Dr. Better.
Overall, the advancement of CAR T-cell therapy is moving at an extraordinary rate. According to a new market research report, the global regenerative medicine market, which was worth $16.4 billion in 2013, is expected to reach $67.6 billion by 2020. Kite hopes to have approval to treat patients with its engineered T-cells in 2017.
The biggest challenge in all of this is that every step taken in this area is new, potentially paving the way for how industry will develop and manufacture these products in the future. Therefore, no time is more important than the present, not just for the companies entering this market but also for the lives that are waiting to be saved. “That’s both the excitement and the challenge,” says Dr. Better. “It’s what keeps us going. There is tremendous therapeutic potential, but the path isn’t clear yet. We’re paving it every day.”