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CAR T-cell therapy uses the patient’s own immune cells to personalize cancer immunotherapy.
What Is CAR T-Cell Therapy?
CAR T-cell therapy is a cancer treatment that uses a patient’s own immune system cells, called T cells, after these cells have been modified to better recognize and kill the patient’s cancer. The T cells are engineered in the laboratory and then expanded to large numbers and infused back into the patient. This type of treatment transfers an immune system into the patient that is capable of immediately killing the cancer. CAR stands for chimeric antigen receptor, which represents the genetically engineered portion of the T cell. The CAR part of the T cell contains proteins that allow the T cells to recognize the specific cancer cells as well as become highly activated to kill the cancer cells.
Once in the body, the CAR T cells can further grow to large numbers, persist for long periods of time, and provide ongoing tumor control and possible protection against recurrence.
How Are CAR T Cells Made for Each Individual Patient and Administered?
The first step is to collect the patient’s T cells from their blood using an outpatient procedure known as leukapheresis. These T cells are shipped to the laboratory for modification and manufacturing. The CAR-containing T cells are then returned for reinfusion into the patient. This process takes about 2 weeks. During the time that the cells are being developed, the patient will typically receive specific chemotherapy that can help prepare the immune system to support the CAR T cells once they are given back to the patient.
Possible Adverse Effects of CAR T-Cell Therapy
CAR T cells are administered in the hospital, where the patient can be monitored closely. Patients receiving CAR T-cell therapy typically develop temporarily low blood cell counts from the treatment, with fatigue, risk of infection, and need for transfusion support. Some patients may also have some of their normal immune cells, called B cells, destroyed as bystanders of the treatment, causing a condition called B-cell aplasia. Because B cells normally make antibodies to protect people from infections, people with B-cell aplasia need to have antibodies periodically given by vein.
In addition, there are 2 significant adverse effects that can occur after CAR T-cell therapy, both potentially serious: cytokine release syndrome (CRS) and neurologic complications. Patients with CRS typically develop a fever, rash, headache, and changes in blood pressure. The symptoms of neurologic toxic effects range from headaches to confusion, delirium, and seizures. Though the onset of the symptoms can occur within minutes or hours, they can be seen days to weeks later. The adverse effects are usually reversible, but rare cases of long-term symptoms have been noted. The possible long-term adverse effects may include cardiac dysfunction, bleeding, and kidney and/or liver failure. The management of severe CRS or neurotoxic effects may involve the use of specific drugs to reverse these symptoms.
Current Role
CAR T-cell therapy has received preliminary approval for treatment of children and young adults with a specific form of leukemia that has not been cured with initial chemotherapy treatment. It is being studied in many other cancer treatment settings and may become more widely used based on the results of ongoing clinical research.
For More Information
https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
https://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy
Section Editor: Howard (Jack) West, MD.
The JAMA Oncology Patient Page is a public service of JAMA Oncology. The information and recommendations appearing on this page are appropriate in most instances, but they are not a substitute for medical diagnosis. For specific information concerning your personal medical condition, JAMA Oncology suggests that you consult your physician. This page may be photocopied noncommercially by physicians and other health care professionals to share with patients. To purchase bulk reprints, call (312) 464-0776.
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Published Online: September 7, 2017. doi:10.1001/jamaoncol.2017.2989
Conflict of Interest Disclosures: None reported.
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CAR T-Cell TherapyA Microcosm for the Challenges Ahead in Medicare
JAMA. Published online July 29, 2019. doi:10.1001/jama.2019.10194
The search for more effective and less toxic therapies for cancer has occupied scientists for decades. Recently approved treatments involving the genetic modification of a patient’s own T cells to better target cancer cells are an important advance in cancer treatment, thereby sparing patients less effective therapies while offering a meaningful chance at remission. Chimeric antigen receptor (CAR) T cells involve the ex vivo transduction of T cells so they express a receptor on their surface that both is specific for a tumor antigen and contains T-cell activation domains such that engagement of the receptor by tumor antigen results in activation of the T cell against the tumor cell. The 2 approved CAR T-cell products include axicabtagene ciloleucel, manufactured by Kite Pharma, and tisagenlecleucel, a Novartis product. Both therapies target CD19 on the surface of B lymphocytes and are approved as single infusions for the treatment of relapsed and refractory B-cell malignancies, including B-cell acute lymphoblastic leukemia (B-ALL) in children and young adults (tisagenlecleucel) and aggressive B-cell non-Hodgkin lymphoma (B-NHL) (both tisagenlecleucel and axicabtagene ciloleucel). Even though these cell therapies produce durable remissions in some patients with no existing effective options, they are priced at a 1-time cost of $475 000 for B-ALL and $373 000 for B-NHL. Countries around the world are grappling with the cost of these treatments.
CAR T-cell therapy is not the first treatment to present health care payers and policy makers with difficult choices about coverage and reimbursement; however, this treatment represents a significant escalation in these challenges. Ensuring equitable and affordable access to CAR T-cell therapy is an important policy goal; development of appropriate policies that anticipate and encourage similar innovations in the future is critical. As the largest payer for cancer care, Medicare is at the center of this discussion. CAR T-cell therapy can be used as a lens through which to examine the larger health policy challenges that high-cost innovation will bring to Medicare and, by extension, other payers.
The What and Why of CAR T-Cell Therapy
Before CD19-directed CAR T-cell therapy, the response rate of available and experimental agents in multiply relapsed and refractory pediatric B-ALL and aggressive B-NHL was approximately 20% to 40%, and response duration was short.1-3 Tisagenlecleucel definitively improved this outcome in pediatric B-ALL, with minimal residual disease–negative complete responses occurring in 61 (81%) of 75 patients; event-free survival and overall survival at 1 year were 50% and 76%, respectively.4 Median overall survival of existing agents in this line of therapy for refractory pediatric B-ALL would normally be 13 weeks to 7.5 months.1,2 In adults with aggressive B-NHL, axicabtagene ciloleucel led to responses in 84 (83%) of 101 patients, with 58% of patients having a complete response.2,3 The ZUMA-1 study has a median of 27.1 months of follow-up, and 39 (39%) of 101 patients treated remain in response at 2 years (ZUMA-1 studies).5,6 Without such treatment, response would be an estimated 26%, with only 7% of patients achieving a complete response.3 These therapies carry risk related to the activation and expansion of immune effector cells on reinfusion, and 20% to 30% of patients require admission to the intensive care unit. The cost of care, then, can be even greater than the price of the products.
Next-generation CAR T cells to target B-cell malignancies are already in development. Some of these aim to improve efficacy by targeting known mechanisms of resistance; others aim to minimize toxicity, utilizing new receptors or new requirements for multiple cell-to-cell interactions between the T cell and the tumor cell to more precisely and physiologically activate an antitumor immune response. CAR T cells are also being tested earlier in a patient’s disease history, when this therapy may prove to be even more effective. In addition, the applicability of CAR T cells and other engineered cellular therapies is expanding, with promising CAR T cells that target the tumor antigen B-cell maturation antigen in multiple myeloma7 and engineered T-cell receptor T cells in development for treatment of a variety of solid tumors. The number of patients eligible for this type of therapy could increase substantially.
Current Coverage and Reimbursement Environment
CAR T-cell therapy is presenting significant challenges to the financial health of hospitals and payers and equitable access to treatment. According to advocacy groups and commentary during Centers for Medicare & Medicaid Services (CMS) hearings, some hospitals report setting limits or declining to offer CAR T-cell therapy at all because of reimbursement concerns. While most private payers have developed policies to cover CAR T-cell therapy, few have established contracted rates with hospitals. Instead, single case agreements are negotiated for each patient meeting US Food and Drug Administration (FDA) eligibility criteria.
Medicare coverage and reimbursement for CAR T-cell therapy are more complex. Recently, at the request of a large Medicare Advantage plan, CMS issued a proposed national coverage determination to cover CAR T-cell therapy only when prescribed by a certified hospital or cancer center and only for treatment of patients with relapsed or refractory malignancies using the patient’s own cells. Many experts have argued that the proposal is overly prescriptive and likely to be quickly outdated. In addition, the proposed coverage decision requires reporting of clinical and patient-reported outcomes that are redundant with the existing reporting and accreditation generally required to administer this therapy.
Currently, hospitals can bill for CAR T-cell therapy under Medicare Part A using the autologous transplant Diagnosis Related Group (DRG). Because the costs of treatment far exceed the DRG amount (currently about $40 000), most hospitals can trigger the outlier payment process. These payments are calculated as 80% of the difference between the product of the total claims multiplied by the hospital’s cost-to-charge ratio and an outlier threshold (which is currently about $26 000 above the DRG amount). A new technology add-on payment has also been established for a limited period to provide some temporary relief while CMS collects charge data to inform future reimbursement policy. The new technology add-on payment is capped at 50% of the product cost of $373 000, or $186 500, which is fully accessible only if the hospital marks up the product. Therefore, for patients with Medicare, a hospital could collect anywhere from less than $150 000 to somewhat more than $400 000 for CAR T-cell treatment depending on the markup placed on the product. Whether this would cover the actual cost of providing the treatment or even result in a “profit” for the hospital or payer is unknown, since this type of information is based on many assumptions, and true cost is rarely transparent. An increase in the new technology add-on payment cap is under consideration by CMS, but this will have little effect on reimbursement to hospitals.
CAR T-Cell Therapy and Medicare Policy
The emergence of CAR T-cell therapy as a breakthrough cancer treatment brings into relief a number of long-standing questions in Medicare policy.8 In contrast to the proposed restrictive coverage policy, experts have recommended coverage for any current FDA-approved indications to maintain flexibility and relevance as the field quickly evolves. Given that Medicare has chosen to cover CAR T-cell therapy, reimbursement should be accomplished more directly than through the complex system of outlier payments. Medicare and other payers should consider allowing hospitals to pass through the manufacturer’s price for cell therapy without a markup both to avoid access problems (with underpayment) and also to avoid the inflationary incentives that markups create. Furthermore, Medicare should adopt a site-neutral (ie, one that does not favor inpatient care) reimbursement model to allow the care team to select the optimal treatment site for patients, potentially reducing cost while being reimbursed fairly. In addition, while product pricing has so far been left to the market, CAR T-cell therapy and future cellular therapies’ substantial health benefits and potential for lower long-run costs in the avoidance of less effective treatments for some patient subgroups suggest the desirability for explicit consideration of clinical outcomes and value in pricing these therapies.9
Another question that CAR T-cell therapy amplifies is whether unrestricted access to some treatments is simply unaffordable. While CAR T-cell therapy is currently indicated for a relatively small subgroup of cancers (fewer than 10 000 cases per year), should the currently approved or future products be proven effective for other types of cancer or first-line use, it is likely that the associated total cost could exceed even Medicare’s ability to pay. In that event, federal policy makers would need to control spending through price, quantity, or both. It would seem most appealing to begin by trying to lower prices through negotiation with manufacturers or stimulating competition. CAR T-cell therapy is an inherently resource-intensive therapy to produce, however, suggesting an upper bound on savings that can be achieved through lower prices. Reimbursement that is inadequate to cover hospital costs of providing CAR T-cell therapy is already leading to rationing of care. More explicit (and more equitable) prioritization of certain uses over others might ultimately be required to manage affordability.
In light of the promise that the next generation of CAR T-cell products holds, it is vital that the coverage and reimbursement policies of the federal government allow for appropriate and equitable access while adapting to support the growth and evolution of this field. At the same time, CMS cannot ignore the affordability constraints that future developments will bring. Indeed, CMS and its health plan partners have clearly recognized these dilemmas and are already looking for ways to balance competing goals. Addressing these challenges thoughtfully may be as critical to achieving the goals of the Cancer Moonshot program as the scientific and clinical developments to date.
Corresponding Author: Meredith B. Rosenthal, PhD, Department of Health Policy and Management, Harvard T. H. Chan School of Public Health, 677 Huntington Ave, Kresge Bldg, Room 408, Boston, MA 02115 (mrosenth@hsph.harvard.edu).
Conflict of Interest Disclosures: Dr Jacobson reports having received honoraria from Kite, Novartis, Humanigen, Precision Biosciences, Bayer, and Celgene and research funding from Pfizer. No other disclosures were reported.
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