Andrew L. Pecora, MD
The hallmark of an antigen-specific response is when T cells recognize and attack an invading pathogen. This same phenomenon occurs in some but not all cancers. The process of neoplasia, which is the development of abnormal cell genomes, results in production and expression of neoantigens that elicit a similar T-cell–mediated response. Once activated against specific antigens, T cells will consume cells that express the antigen until all are eliminated or the T-cell response is turned off via checkpoints.
As the lead story in our upcoming September issue of Oncology Business Management will discuss, a new industry is forming based on our ability to block such checkpoints and enable the antigen-specific T cells to remain active; finish off malignant cells; and, potentially, cure the patient. However, not all tumors express antigens for which a complementary T-cell receptor may conveniently exist to initiate an antigen-specific immune response. Sometimes there are just too many tumor cells for in vivo T-cell generation to succeed. To overcome these limitations, scientists began to manipulate T cells through gene therapy in the early 1980s, leading to the development of functional chimeric antigen receptor T (CAR T) cells in 1989.
To have a specific antigen receptor expressed on the surface of a T cell, genetic engineers created DNA constructs that coded for monoclonal antibodies and inserted them into T-cell DNA using retroviral carriers. Once translated into the DNA, the monoclonal antibody expressed a receptor on the T-cell surface with specificity to the antigen expressed by a target malignant cell. Clinical trials have shown CAR T cells to be highly effective in eliminating cancer cells in some patients and seemingly curing those whose malignancy had failed all prior therapies, including bone marrow transplant. There are drawbacks to this therapy. Severe and life-threatening toxicities have occurred because the CAR T cells released cytokines that caused extensive tissue damage; in some cases, the CAR T cells recognized antigens on vital organs such as the heart and attacked, resulting in the death of the patient. However, there is no doubt that for select patients, CAR T cells will be the only real hope for cure of an otherwise incurable disease.
One can only imagine how complex and expensive it will be to mass-produce these cells for clinical use. So, despite all the excitement and anticipation, there is a growing anxiety among payers and providers: “What will CAR T cells cost?” Early estimates are in the hundreds of thousands of dollars. Soon, the warning bell will ring, and everyone will demand explanations for why these modified cells cost so much. Will this be another example of a high-flying technology that is overused and won’t add value to healthcare? I think not, but we must be cautious. The expense and complexity of this therapy demand that it work most of the time and replace another costly procedure—bone marrow transplantation. It is comforting to know that manufacturers of these products are considering value-based reimbursements, requiring payment only if the therapy eradicates all detectable cancer cells. In addition, this product must eliminate the need for other products and services so that revenues and expenses stay in balance. In prior days, if you could not afford a car, you walked. Here, you may not be able to not afford a CAR T cell if your life depends on it, so we must find a place for CAR T cells in our healthcare budgets.