The recent FDA approvals of a cell/gene therapy for patients with advanced B cell malignancies provide a glimpse into a paradigm shift in the treatment of hematologic and solid cancers, the creation of a new drug unique to each cancer patient.
In 2010, the Surgery Branch at the National Cancer Institute first reported the regression of advanced lymphoma in a patient infused in 2009 with his own lymphocytes genetically engineered to express a chimeric antigen receptor (CAR) that recognized CD19, a cell surface molecule expressed on B cell malignancies and normal B cells.
This patient experienced a complete cancer regression that has lasted over 8 years. Other groups at Memorial Sloan Kettering Cancer Center, the University of Pennsylvania and other academic medical centers demonstrated similarly impressive results with CD19-CAR T cells in patients with B-cell malignancies leading to multi-institutional trials sponsored by Kite Pharma and Novartis. The CD19-CAR T cell approach became the first cell and gene therapy approved by the FDA for patients with cancer.
Immunotherapy using a patient’s own anti-tumor lymphocytes, naturally arising in the host or genetically engineered in the laboratory to attack cancer, is a new approach to drug development that represents a convergence of work in two areas of immunotherapy.
In 1988, we showed that T cell transfer using a patient’s own tumor infiltrating lymphocytes (TIL) expanded in vitro could mediate regression of metastatic melanoma. Refinements to this treatment achieved complete, sustained regressions in about 30% of these patients.
In 2006, pilot studies showed that cancer regression could occur in patients with metastatic melanoma following infusion of autologous, anti-tumor lymphocytes created in the laboratory by transduction of genes encoding highly avid T cell receptors (TCRs) that recognized shared, non-mutated melanocyte antigens such as MART-1 and gp100.
Severe autoimmunity was observed in these trials due to the expression of these antigens on normal melanocytes in the skin, eye and ear. Tumor regression and severe colitis were seen in colon cancer patients receiving T cells transduced with genes encoding TCRs that recognized non-mutated carcinoembryonic antigen (CEA) thus emphasizing the difficulties encountered when targeting antigens expressed on normal tissues.
The lack of normal tissue toxicities seen in melanoma patients responding to TIL administration thus led us to explore the role of cancer mutations as possible cancer antigens.
To identify the prevalence of possible cancer antigens on common epithelial cancers we developed high-throughput screening methods to identify cancer mutations that were immunogenic, i.e. recognized by the patient’s T-lymphocytes.
In studies of tumors from over 100 patients with a variety of metastatic epithelial cancer types we found that about 70-80% of patients mounted T cell responses to cancer specific mutations. An average of 1-2 % of mutations in each patient were recognized by the immune system.
Surprisingly, the overwhelming majority of these immune responses arose from random somatic mutations unique to that cancer and not shared by other cancers though rarely shared mutations encoded by “hotspots” in genes known to play a role in oncogenesis, such as KRAS or p53, were recognized.
The targeting of mutated proteins appears to be the “final common pathway” underlying the effectiveness of all natural immunotherapies including IL-2, checkpoint modulators and TIL.
These insights led us to develop immunotherapies based on the transfer of autologous T cells enriched for reactivity against cancer mutations unique to that cancer—a highly personalized treatment in which lymphocytes are used as a new drug unique for each patient.
Whole exome and RNA sequencing of tumor and normal tissue can identify all mutations expressed by the cancer in 10-14 days. Autologous lymphocytes and their TCRs reactive with these mutations can be isolated and used to generate large numbers of tumor-reactive lymphocytes for treatment.
In encouraging early reports using the transfer of mutation-reactive, autologous lymphocytes, objective regressions have been seen in isolated patients with several types of metastatic epithelial cancers including those arising in bile ducts, colon, cervix and breast. Since all cancers contain mutations, this approach is a potential “blueprint” for the treatment of most cancer types.
The creation of an individual drug for each patient represents a considerable departure from the established norm in drug development. Traditional pharmaceutical companies depend on the development of “drugs in a vial” applicable to large numbers of patients and easily distributed widely.
The development of the first vial can cost hundreds of millions of dollars and can be commercially pursued if subsequent vials can be produced for a few pennies or dollars. This approach using cytotoxic or targeted agents has largely failed to cure patients with metastatic solid tumors, and. although life can be prolonged, virtually all patients with detectable metastatic epithelial cancers will die of their disease despite the best available treatments.
Existing off-the-shelf immunotherapies have limited efficacy against the common epithelial cancers that kill over 90% of patients that die of cancer in the U.S. every year (estimated to be about 600,000 deaths in 2018). The introduction of checkpoint modulators is an important step in the development of immunotherapy, especially in patients with melanoma, though complete responses remain infrequent for the solid epithelial cancers.
The complexity and expense of individualized cancer treatments have discouraged large pharmaceutical companies from developing the new cell-based strategies described here. Further complexity derives from the need to utilize natural TCR-based rather than simpler CAR-based treatments. CARs depend on the antigen binding properties of monoclonal antibodies and can only target the subset of proteins expressed on the cell surface and these are very rarely mutated.
It has been over 40 years since the description of monoclonal antibodies and, despite considerable effort, none have been found uniquely reactive with shared antigens on the surface of cancer cells from solid tumors. Targeting non-mutated cell surface proteins can lead to life-threatening destruction of normal tissues.
The biology of cancer is complex and effective treatments may involve more than swallowing a pill or receiving the infusion of a “one-fits-all” drug. Infusion of anti-tumor lymphocytes is a “living treatment” often administered only once since the anti-tumor cells can expand a thousand-fold in the week after administration and survive in the patient for years.
Cell therapies will be expensive, but medical care dollars can be saved if curative treatments can be developed using this approach rather than having patients spend hundreds of thousands of dollars to move from one expensive, minimally effective treatment to another.
The developmental stages of cell therapies for cancer have largely been performed by academic groups that face increasing obstacles to progress. Many research institutions seeking to develop and improve cell therapies require investigators developing individual treatments for a single patient with a lethal disease to meet Good Manufacturing Practice regulations similar to those required by drug companies preparing a “one-size-fits-all” drug for millions of patients.
Immunotherapy using a patient’s own antitumor lymphocytes, naturally arising in the host or genetically engineered in the laboratory to attack cancer, is a new approach to drug development that represents a convergence of work in two areas of immunotherapy.
These institutional requirements appear to exceed guidance by the FDA that allow more flexibility for small academic groups engaged in phase I cell transfer studies for limited numbers of patients. The FDA guidance is vague, however, and clarification by the FDA of the requirements for cell transfer investigative trials could unleash additional clinical research in this area.
Related to this issue is the need for the development of automated, “hands-off” techniques for the many repetitive manipulations involved in the identification, isolation and growth of mutation-reactive lymphocytes.
The generation and administration of cells at each institution to treat their own patients is necessary for discovery and innovation in cell-based therapies but is not likely to bring personalized cell therapies to large populations in need since for this purpose each institution would have to develop and validate their own procedures and receive Investigational New Drug (IND) approval from the FDA, a laborious, expensive and time-consuming process beyond the means of most clinical centers. A practical model for treatment, pioneered by Kite Pharma and Novartis, is the development of central laboratories that can receive lymphocytes and/or tumors and prepare the “personalized drug” as cryopreserved cells for delivery to the home institution for infusion.
The exquisite specificity and sensitivity of the immune system, capable of recognizing single amino acid changes in a long intracellular protein has opened a new paradigm in cancer treatment—the ultimate “personalized” therapy using a patient’s own cells to recognize mutations unique to the patient’s cancer.
Much remains to be done to make this new approach better, simpler and faster. In the 16th century, Francis Bacon, a philosopher/scientist, warned, “Ye that will not apply new remedies must expect new evils for time is the great innovator.”
The views expressed here are my own and do not necessarily reflect the views of the NCI or NIH.
