Despite great strides in developing novel therapies and treatment paradigms for cancer patients, cancer prevalence is expected to increase worldwide in the coming years. In 2018, an estimated 1.7 million new cases of cancer will be diagnosed in the United States alone and 609,640 people will die from the disease. Estimated national expenditures for cancer care in the United States in 2017 were $147.3 billion, and are expected to reach $174 billion by 2020, second only to cardiovascular disease. Current therapies provide clinical benefit and extend life expectancies for cancer patients, and in the process necessitate ongoing medical visits and support to manage the cancer as a chronic disease. There exists a critical need for novel therapies that provide long term effective cancer control without the need for sustained supportive care.
Immunotherapy (harnessing the immune system to recognize and destroy cancerous cells) has provided new hope for achieving improved outcomes and long term survival without the need for chronic supportive care. The potential for the immune system to recognize, destroy, and “remember” cancerous cells has long been appreciated but only recently translated to clinical practice. Long term tumor control has been observed in certain cancers treated with antibodies that promote T cell mediated cancer cell killing (eg; pembrolizumab), providing direct evidence that T cells can mediate potent and long-lasting tumor control. Recent breakthroughs in cell-based immunotherapy stem from innovative approaches that combine the highly selective targeting nature of antibodies with the potent inherent cell killing capacity of the T cell. Good examples of chimeric antigen receptor (CAR) T cell-based immunotherapy include Yescarta and Kymriah, both FDA-approved CAR T cell therapies that target a surface protein (CD19) expressed on B cell lymphoma and normal B cells. When infused into patients with lymphoma, the CAR T cells actively target and destroy CD19+ lymphoma. Normal B cells are also eradicated, but this can be managed through regular infusions of immunoglobulin. Clinical results to date have been highly encouraging, with evidence of long term tumor control in a subset of patients. However, there are limitations to CAR T therapy, including serious potentially life threatening side effects associated with rapid and robust large scale T cell activation following infusion, including fever and organ toxicity due to the high levels of cytokines released. CAR T cell therapies are also generally limited to a relatively small number of cancers for which a defined surface antigen can be targeted. To overcome these limitations, next-generation T cell-based immunotherapies are being developed that take advantage of the inherent capacity of the T cell receptor (TCR) to recognize small peptides (antigens) derived from diverse sources, including intracellular proteins. This feature is expected to extend T cell immunotherapy to multiple cancer types, including solid tumors that may not be as readily amenable to a CART based immunotherapy.
The basic manufacturing principles for producing CAR-based and TCR-based T cell immunotherapies are similar, but both require rapidly evolving and sophisticated processes that require specialized equipment and expertise that are not readily available to the physician scientists, clinicians and companies actively engaged in the development of these therapies. As a consequence, scientific advances with great clinical potential are outpacing the infrastructure and technical capabilities needed to support rapid development and clinical evaluation.