CAR T-Cell Therapy: A Healthcare Professional's Guide - Commercialization

Chimeric antigen receptor (CAR) T-cell therapy is the first form of gene therapy approved in the U.S. CAR T-cell therapy works with the patient's own immune system to help boost the cancer-killing effects of the T lymphocyte (T-cell), a white blood cell. It's a complicated engineering process of the T-cell. It is not a chemotherapy as traditionally used in cancer treatment.

CAR T-cell therapy is approved in patients with relapsed and refractory malignancies such as lymphomas and leukemias. The first approval, Kymriah (tisagenlecleucel), was approved for pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). These patients have run out of viable options for cancer treatment, which include surgery, radiation, chemotherapy, and bone marrow transplant. In May 2018, Kymriah was also approved for relapsed or refractory large b-cell lymphoma in adults after two or more therapies.

The processes required to gather the T-cells (apheresis), attach the CAR T receptor via genetic engineering, and then re-infuse the cells back into the patient is a long, complex and expensive process. However, the question remains -- will these products be commercially viable and accessible by patients? How will insurance pay for these treatments? What will be the patient's responsibility in paying?

• Learn More: CAR T-Cell Therapy: A Healthcare Professional's Guide - Mechanism of Action

• Learn More: CAR T-Cell Therapy: A Healthcare Professional's Guide - Manufacturing

As pointed out in AJMC, challenges to commercialization include:

• Maintaining accredited Good Manufacturing Practice (GMP) facilities for CAR T-cell manufacturing.
• Ongoing monitoring of very fragile patients.
• Shortening the manufacturing time from apheresis to eventual re-infusion to the patient, currently about 2.5 to 3 weeks.
• Freezing and cryogenic transportation of CAR T-cells once engineered with the CAR construct receptor.
• Ongoing education for health care providers, patients and families

Manufacturing a patient-specific product such as this is difficult to scale in order to lower production costs. However, research is ongoing to develop "off-the-shelf" or universal CAR T-cells that could reduce costs, and, even more importantly, hasten delivery to cancer patients who may have no other treatment options.

Learn More: CAR T-Cell Therapy: A Healthcare Professional's Guide - Adverse Events

The timing and delivery logistics of CAR T-cell therapy could be taxing for the healthcare system:

• Academic and larger tertiary care centers are expected to be CAR T-cell centers of excellence; patients will need referral from their local oncologists to be treated at these specialized facilities.
• Travel expenses, transporation, and boarding for patients, families and other caregivers may lead to added financial hardships.
• A medical referral and insurer prior authorization process would be expected. For such a complicated and costly treatment, patients will be reviewed by payers to determine prior treatments and clinical eligibility. A quick turnaround review time will be important for these fragile patients.
• The time from apheresis, to manufacturing, to re-infusion of engineered CAR T cells back into the patient can range from 2.5 to 3 weeks; some patients may not tolerate this extended period. However, manufacturers are implementing continuous quality improvement processes to shorten this production time.

Education for patients, families, and health care providers will be a large component of CAR T-cell therapy. The complicated mechanism of action, manufacturing process, administration, risks, side effects, and cost issues will need to be adressed.

In this fragile and very sick patient population, serious adverse reactions such as:

• Cytokine release syndrome
• Neurotoxicity
• Cerebral edema
• B cell aplasia

require immediate medical attention. Nursing staff, as well as family members, must be able to recognize these dangerous complications, as there may be a delay in some side effects. However, researchers have dealt with many of these side effects in bone marrow transplant patients.

The approved CAR T-cell therapies, Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel), are only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Kymriah REMS and the Yescarta REMS. These programs are in place to help lower the patient's risk for serious, possibly fatal, adverse events.

Learn More: CAR T-Cell Therapy: A Healthcare Professional's Guide - Cancer Targets

A patient-specific and complicated manufacturing process such as CAR T is expected to be costly. The cost of the first CAR T cell therapy from Novartis is set at $475,000 per treatment according to Novartis. Only one treatment is needed. Kite Pharma/Gilead has said their single CAR T therapy will run $373,000 per treatment regimen. The commercial potential of CAR T-cell therapy could exceed $1.5 billion by 2020.

Specialized facilities and healthcare providers, manufacturing costs, the possible need for intensive care post-infusion due to serious adverse events, and prolonged hospitalization are costs linked with this therapy.

What about reimbursement? Feinberg and colleagues suggest that a bundled payment approach, where a limited number of facilities offer treatment with contractual payment agreements may be one reimbursement strategy, similar to the current precedent set by allogeneic HSCT.

As reported by FiercePharma, Novartis "has already established an outcomes-based approach to reimbursement for Kymriah with the Centers for Medicare and Medicaid Services (CMS) that allows for full payment only when these patients respond to Kymriah by the end of the first month after treatment." Patient assistance for uninsured and underinsured patients is also in place.

However difficult or expensive the therapy is, the success rate of CAR T cell therapy has been impressive in patients with refractory leukemias and lymphomas, with some response rates in the 80% range.

• Learn More: CAR T-Cell Therapy: A Healthcare Professional's Guide to KTE-C19 Studies

Allogenic CAR T-cell production, otherwise known as "off-the-shelf" or "universal" T-cell therapy, is under investigation. Creating a universal CAR T agent could help avoid the lengthy and sometimes dangerous time period from apheresis of T cells to re-infusion, which can be weeks. Some patients are too sick to withstand this long time period until re-infusion. In fact, some patients cannot tolerate apheresis at all.

As reported by Kite Pharma in July 2016 and April 2017, they have partnered with the University of California Los Angeles (UCLA) to advance the technology needed to develop "off-the-shelf" allogenic T-cell therapies.

Research, led by Gay Crooks, MD at UCLA, involves an artificial thymic organoid (ATO) cell culture system that replicates the differentiation of T-cells ex vivo. The ATO system potentially can support the "efficient and scalable production of T-cells using pluripotent stem cell lines capable of indefinite self-renewal." Pluripotent stem cells have the ability to differentiate into many different cell types, including T-cells. In addition, technology to include chimeric antigen receptors, T-cell receptors, and other gene modifications can be incorporated into the T-cells. Kite holds the exclusive license to the ATO cell technology from UCLA.

According to Kite, the commercial-scale production of T-cells via culture in vivo have been hindered by low output of T-cells and donor-to-donor variability. However, it still remains to be seen if allogeneic "off-the-shelf" T-cell products will be as robust as autologous CAR T-cell therapies. Research in this area will continue at a fast pace.

In addition, the use of natural killer (NK) cells are under study at MD Anderson in Houston. CAR NK cell studies are targeting acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, but could potentially be used for other cancers, including solid tumors. Creating a bank of allogeneic NK cells could be an advantage for patients who cannot wait for the creation of personalized therapy from their own T-cells, and greatly lower the risk for graft-versus-host disease (GVHD) that can be seen with allogeneic T-cells.