June 15, 2018
Pioneering endogenous T-cell therapy for cancer treatments
BY Clayton R. Boldt, Ph.D.
Immunotherapy, which stimulates the patient’s own immune system to attack cancer, has shown promise in treating a variety of cancer types with long-term responses. This class of therapy involves a range of treatments, including checkpoint blockade inhibitors, vaccines and cell-based therapies.
MD Anderson’s adoptive-cell therapy (ACT) platform, which supports the Moon Shots Program™ was established to develop promising new cell-based immune therapies to treat patients with greatest need. The Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives, established 10 research platforms to provide unique expertise, technical support and novel infrastructure to support the program’s disease-focused initiatives.
Cassian Yee, M.D., professor of Melanoma Medical Oncology and Immunology, and co-leader of the ACT platform, has pioneered the use of endogenous T-cell therapy for treating cancer. He spoke with Cancer Frontline about those efforts.
Q: Can you briefly describe the concept of adoptive-cell therapy?
A: Adoptive-cell therapy is a form of immunotherapy which involves the isolation and expansion of immune cells in the lab so that they can be infused back into patients for the treatment of cancer. Unlike chemotherapy, surgery or radiation, immune therapy uses the body’s own immune system, providing multiple ways of killing cancer cells and enabling long-term protection against recurrence.
Science and technology have progressed so rapidly in the last five to 10 years that ACT is becoming the treatment of choice for some cancers that fail conventional treatment. There has been a ‘renaissance’ in ACT recently. As recently as five years ago, we could not fill a small classroom with people interested in hearing about ACT, but today general cancer meetings like ASCO are filled to capacity for ACT presentations.
Q: Can you explain the different types of cell-based therapies and how they work?
A: When most people refer to ACT, they are speaking about T-cell therapy. Some ACT approaches use another type of immune cell, natural killer (NK cells), and our ACT platform also is doing exciting work in this area.
For now, I’ll focus on the three forms of ACT that use T cells: tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR) T-cell therapy, and my area of focus, endogenous T-cell (ETC) therapy.
With TIL therapy, tumor-reactive T cells are taken from a patient’s tumor and expanded in the lab with an immune signaling molecule, IL-2, before being infused back into the patients to attack their tumor. CAR T-cell therapy involves genetically engineering T cells so that they recognize a specific tumor antigen.
ETC therapy is unique in that it requires neither tumor as a source of T cells (like TIL) nor genetic engineering (like CAR T cells). Rather, ETC relies on naturally occurring tumor-reactive T cells in the peripheral blood, an advantage of this technique. In general, these cancer-killing T cells are exceptionally rare and require labor-intensive methods to isolate and expand them before giving them back to a patient.
However, our group has developed techniques to do just that, and we have isolated and expanded T cells specific to several antigens found on many cancer types, including pancreatic, ovarian, lung, colorectal, gastric, uveal melanoma and sarcomas. Our approach allows us to rapidly deploy therapy without requiring genetic engineering or surgical access to the tumor.
Q: How have you been able to overcome the challenges associated with ETC therapy?
A: ETC is like a ‘dark horse’ in the field of ACT. Historically, it was not at all favored by researchers in the field because it was very labor- and personnel-intensive.
Tumor-reactive cells in the peripheral blood are found at frequencies between one in 100,000 and one in one million, yet they must be expanded to numbers in the 10-20 billion range, with a uniformity of greater than 90 percent, for ACT.
Therefore, we had to develop specialized technologies over the last 20 years to isolate and expand those rare T cells. To do this, we pioneered the use of a clinical-grade cell sorter and a reagent to select antigen-specific T cells from a short-term cell culture, which was conditioned with a specialized cocktail which enriches for the growth of long-lasting memory T cells.
We were early adopters of ETC and were very fortunate then in terms of exploratory funding to help us develop these techniques. We’ve also been able to exploit a number of new technologies over the years that will help bring a relatively boutique therapy to the mainstream. What used to take us 12 weeks now only requires six to seven weeks, and we hope to bring it down to four weeks by next year.
Q: What success have you seen with using ETC therapy in the clinic thus far?
A: We have achieved complete and durable responses in patients with metastatic disease failing conventional therapy, and even those failing immune checkpoint therapy, suggesting that the combination of T cells and immune checkpoint therapy is important.
However, these trials include relatively small numbers of patients and will need to be repeated in trials with larger numbers to evaluate the true efficacy of ETC therapy.
Q: What future plans do you have for expanding the use of this technique in treating other cancers?
A: We are initiating several early-phase studies with a number of clinical investigators here at MD Anderson like Adi Diab, M.D., and Sapna Patel, M.D., in skin and eye melanoma; Amir Jazaeri, M.D., in ovarian cancer; Neeta Somaiah, M.D., in sarcoma; Shubham Pant, M.D. and Michael Overman, M.D. in pancreatic cancer; and Vassiliki Papadimitrakopoulou, M.D. and Vincent Lam, M.D., in lung cancer. In addition, the work of Greg Lizee, Ph.D., in antigen discovery has enabled us to extend the reach of ETC to many cancer types.
Without these individuals, the clinical base and clinical trial infrastructure at MD Anderson, these critical, first-in-human entry studies for patients that have not benefited from conventional therapy, using this new ACT modality would not be possible.
Some of this technology also has resulted in a spin-off company, Immatics US Inc., now engaged in clinical trials of ETC for a broad range of cancer types at MD Anderson.
Q: How has the Moon Shots Program and the ACT platform made this work possible?
A: The Moon Shots Program funding has been directly responsible for rapidly implementing clinical trials that would otherwise take six to 18 months to get started if we relied upon alternative funding sources.
The ACT platform provides critical personnel infrastructure, not only for handling the cells, but also for regulatory and administrative components which oversee brand new technologies and ‘biologicals’ that the FDA is not accustomed to.
As a leader in the field of ACT, MD Anderson has a stake in seeing that we get novel effective therapies to patients as safely and as quickly as possible. The Moon Shots Program and ACT platform are doing that for cell therapies.