Chimeric Antigen Receptor T-Cell Therapy (CAR T-Cell Therapy)

January 24, 2018

While the healthcare market is being called upon to reduce costs, the cost of treating cancer continues to climb as new cancer solutions emerge.

Background

As the population ages, the risk of being diagnosed with cancer substantially increases.  According to the Dana-Farber Cancer Institute half of all cancers occur at age 66 and above[1]. While the healthcare market is being called upon to reduce costs, the cost of treating cancer continues to climb as new cancer solutions emerge. Historically, the treatment for cancer has been surgery, chemotherapy, and radiation therapy. In the last 20 years, we progressed to targeted drug therapies called monoclonal antibodies that target cancer cells by homing in on specific molecular changes seen primarily in those cells. These therapies have also cemented themselves as standard treatments for many cancers.

However, over the past several years, a treatment called immunotherapy has surfaced as a new cancer fighting therapy.  It works by using a patient’s own immune system to attack tumors. There are many approaches to immunotherapy, but they all work by using the body’s own defenses to identify and attack cancer cells. Immunotherapy can try to boost your body’s overall immune response or it can enable your immune system to recognize and fight cancer. The drugs or agents used can be substances made by your own cells or agents made in the lab.

The immune system works in many ways to identify unhealthy cells and foreign invaders (such as viruses and bacteria) and attack them. Researchers have known for years that our bodies can recognize cancer cells as abnormal and then destroy them. Often, cancer cells have molecules on their surface that can be detected by the immune system. T cells recognize peptide antigens ‘presented’ on their cell surface. If pre-cancerous cells present abnormal proteins, T cells will recognize these cells as abnormal. Conversely, pre-cancerous cells that the immune system does not recognize as abnormal, or is unable to kill, will survive and may proliferate to form a tumor.

There are myriad ways that tumor cells may use to get around the immune defenses of the body. Many cancers produce chemical messengers that inhibit the actions of immune cells. Other cancers have defects in the way that antigens are presented on their cell surface. Other immune cells, called natural killer (NK) cells, play a special role, however, because they notice when body cells no longer have present specific ‘self’ proteins on their surface and kill the abnormal cells. Additionally, some tumors grow in locations such as the eyes or brain, which are not regularly patrolled by immune cells.

The main goal of immunotherapy and cancer vaccines is to provide the immune system with the signals that it needs to recognize the cancer cells as abnormal. If successful, these strategies may allow the body to recognize and destroy cancer cells, even those that have been able to form a tumor

The concept of using the body’s own defenses to fight cancer is not new, but earlier attempts to develop immunotherapies were not very successful. Because researchers now better understand the complex interaction between the immune system and cancer, this information is being put into practice as physicians are developing new ways of using the immune system to fight cancer. New immune-therapies include: monoclonal antibodies that target specific features of cancer cells, adoptive T-cell transfer therapy (such as CAR T- Cell Therapy) that uses re-engineered immune cells to help the immune system work better, checkpoint inhibitors that stop cancer cells from turning off the immune system, cancer vaccines that help the body’s defenders recognize and destroy cancer cells and oncolytic viruses that use modified viruses to kill cancer cells.

There are several types of adoptive T-cell transfer therapy (TILs, TCRs, and CARs), but in this article we will focus on Chimeric Antigen Receptor T-Cell Therapy also known as CAR T-Cell Therapy.

How Does CAR T-Cell Therapy Work[2]?

T-cells are collected from a patient via apheresis, which is a process that withdraws blood from the body and removes one or more blood components (such as plasma, platelets or white blood cells). The remaining blood is then returned back into the body. T-cells are reengineered in a laboratory and then sent to a laboratory or a drug manufacturing facility where they are genetically engineered to produce chimeric antigen receptors (CARs) on their surface.

After this reengineering, the T-cells are known as “chimeric antigen receptor (CAR) T-cells.” CARs are proteins that allow the T-cells to recognize an antigen on targeted tumor cells. The reengineered CAR T-cells are then multiplied. The number of the patient’s genetically modified T-cells is expanded by growing cells in the laboratory until there are many millions of them. These CAR T-cells are frozen and, when there are enough of them, they are sent to the hospital or center where the patient is being treated. At the hospital or treatment center, the CAR T-cells are then infused into the patient. Many patients are given a brief course of one or more chemotherapy agents before they receive the infusion of CAR T-cells. CAR T-cells that have been returned to the patient’s bloodstream multiply in number. These are the attacker cells that will recognize and kill cancerous cells that have the targeted antigen on their surface. The CAR T-cells guard against recurrence of the cancer and may remain in the body long after the infusion has been completed so the therapy frequently results in long-term remissions.

In addition to the promising benefits, it is important to consider the possible side effects of CAR T-cell therapy.

A serious side effect associated with CAR T-Cell Therapy is cytokine-release syndrome (CRS). CRS is the result of T-cell activation, so its presence actually indicates a positive response to therapy. Cytokines are chemical messengers that help the T-cells perform their duties. With CAR T-Cell Therapy, large amounts of cytokines are produced by the activated immune system. CRS in this setting may cause high fevers, low blood pressure or poor lung oxygenation (requiring administration of supplemental oxygen as a temporary measure). Some patients experience delirium, confusion and seizures while undergoing treatment.[3]

B-Cell Aplasia can also be anticipated. CAR T-Cell Therapy targeting antigens found on the surface of B cells not only destroy cancerous B cells but also normal B cells. Therefore, B cell aplasia (low numbers of B cells or absent B cells) is an expected side effect. This absence of B cells results in less ability to make the antibodies that protect against infection. Intravenous immunoglobulin replacement is used to prevent infection. It is not known how long the decreased number of B cells persists however, no long-term side effects have been noted.

Another known side effect of CAR T-Cell Therapy is tumor lysis syndrome (TLS), a group of metabolic complications that can occur due to the breakdown of dying cells—usually at the onset of toxic cancer treatments. However, TLS can occur one month or more after CAR T-cell therapy. TLS can be a life-threatening complication of any treatment that causes breakdown of cancer cells, including CAR T cells. The complication has been managed by standard supportive therapy.

Specialty Pharmaceuticals

On August 30th, 2017, the FDA approved the first CAR T-Cell Therapy, Kymriah™, for children and young adults up to age 25 with B-cell Acute Lymphocytic Leukemia that is refractory or in second or greater relapse. There has been an urgent need for novel treatment options that improve outcomes for patients with relapsed or refractory (r/r) B-cell precursor ALL, whose prognosis is poor. Patients often undergo multiple treatments including chemotherapy, radiation, targeted therapy or stem cell transplant, yet less than 10% of patients survive five years.

The FDA approval of Kymriah™ is based on the results of the pivotal open-label, multicenter, single-arm Phase II ELIANA trial, the first pediatric global CAR-T cell therapy registration trial, examining patients in 25 centers in the US, EU, Canada, Australia and Japan. In this study, 68 patients were infused and 63 were evaluable for efficacy. Results show 83% of patients who received treatment with Kymriah™ achieved complete remission or complete remission with incomplete blood count recovery within three months of infusion. In addition, no minimal residual disease (a blood marker that indicates potential relapse) was detected among responding patients.

Kymriah™ is offered as a one-time treatment that is expected to cost $475 thousand dollars for the manufacturing of the drug itself. This does not include professional and facility fees related to the administration of the treatment. Other CAR-Ts in development are expected to be similarly expensive which is causing significant concern in the market. In an effort to mitigate these concerns, Novartis is collaborating with the Centers for Medicare and Medicaid Services (CMS) to provide Kymriah™ under an outcomes-based approach which will allow for payment only if patients respond to treatment by the end of the first month.[4]

It is important to note that some patients treated with CAR-T also go on to receive a stem cell transplant, which adds to the treatment cost.  However the goal of Kymriah™ is to eliminate the need for transplant and move towards being a true one-time treatment.

Another further consideration in the associated costs are the drugs needed to help manage the potentially severe side effects associated with CAR-T. Actemra® (tocilizumab), an IL-6 inhibitor, is commonly used in patients who experience cytokine release syndrome (CRS). In approving Kymriah™, the FDA also broadened the label of Actemra® to specifically use for treating CRS in the context of CAR-T treatment.

The FDA has approved a Risk Evaluation and Mitigation Strategy (REMS) for Kymriah™. The REMS program serves to inform and educate healthcare professionals about the risks that may be associated with Kymriah™ treatment. To support safe patient access, Novartis, the sponsor of the trial, is establishing a network of certified treatment centers throughout the country whose staff will be fully trained on the use of Kymriah™ and appropriate patient care. Kymriah™ is expected to be available through a network of these certified treatment centers.

On October 18th, 2017, the FDA approved Yescarta™ (axicabtagene ciloleucel), the second gene therapy approved to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment. Yescarta™, a chimeric antigen receptor (CAR) T cell therapy, is the first gene therapy approved for certain types of non-Hodgkin lymphoma (NHL). It is meant to be given once, infused into a vein, and must be manufactured individually for each patient. The manufacturing cost for Yescarta™ is said to be priced at $373 thousand dollars.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL in adults. NHLs are cancers that begin in certain cells of the immune system and can be either fast-growing (aggressive) or slow-growing. Approximately 72,000 new cases of NHL are diagnosed in the U.S. each year, and DLBCL represents approximately one in three newly diagnosed cases. Yescarta™ is approved for use in adult patients with large B-cell lymphoma including DLBCL, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma after at least two other kinds of treatment failed. Yescarta™ is not indicated for the treatment of patients with primary central nervous system lymphoma.

The FDA granted approval because the safety and efficacy of Yescarta™ was established in a multicenter clinical trial of more than 100 adults with refractory or relapsed large B-cell lymphoma. The complete remission rate after treatment with Yescarta™ was 51 percent.[5]

Yescarta™ has the potential to cause significant side effects. Like Kymriah™, it too can produce cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR-T cells causing high fever and flu-like symptoms and neurologic toxicities. Both CRS and neurologic toxicities can be fatal or life-threatening. Other side effects include serious infections, low blood cell counts and a weakened immune system. Side effects from treatment with Yescarta™ usually appear within the first one to two weeks, but some may occur later.

Because of the risk of CRS and neurologic toxicities, Yescarta™ is also being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). Hospitals and their associated clinics that dispense Yescarta™ will be specially certified. As part of that certification, staff involved in the prescribing, dispensing or administering of Yescarta™ are required to be trained to recognize and manage CRS and nervous system toxicities. Also, patients must be informed of the potential serious side effects and of the importance of promptly returning to the treatment site if side effects develop. To further evaluate the long-term safety, the FDA is also requiring the manufacturer to conduct a post-marketing observational study involving patients treated with Yescarta™.

Researchers are hoping the momentum behind the technology builds as they continue to investigate the abilities of personalized cellular therapeutics in blood cancers and solid tumors to help patients with many other types of cancer. Studies of CAR T-Cell Therapy in other blood cancers, including chronic lymphocytic leukemia (CLL) as well as multiple myeloma, are also very promising.

Treatment and monitoring of these types of therapy will require similar resource and expertise as needed for stem cell transplants. A member, diagnosed with the appropriate condition will travel to a designated treatment center for initial consultation and treatment planning. The member will either return home or remain at the treatment center for ongoing treatment of the disease. Treatment may also occur after a bone marrow transplant, but this is not a prerequisite for the treatment

If the member is appropriate for the treatment, the member will have apheresis or leukapheresis. This treatment may occur either in an inpatient or outpatient setting. The treatment center will place an order for CAR T-cell production and the member’s cells will be shipped to the manufacturer. The member will likely return home for 2-3 weeks during the manufacturing process.

Until infusion of the CAR T-Cell Therapy, the member will likely be receiving chemotherapy in an inpatient or outpatient setting to control disease progression.

After successful manufacturing, the member will receive infusion of the CAR T-Cell Therapy at the treatment center. The member will receive chemotherapy and the CAR T-cell infusion and will be monitored and treated for any complications over a 10 day period either in an inpatient or outpatient setting. The member will need to remain in the area for an additional 1-2 weeks for monitoring.

Financial Implications of CAR T-Cell Therapy

The financial implications of CAR T-Cell Therapy are significant. With drug costs nearing $500 thousand dollars for a single dose (which does not include professional, facility or ancillary service charges), insurers are looking for cost management assistance. There are also many uncertainties related to billing at this time that make predictability challenging. Coding beyond diagnosis related DRG’s has not been established and apheresis, infusions and follow up care may all be done on an inpatient or outpatient basis depending upon facility preference and clinical indications. Indication-based pricing, where similar treatments are priced differently based on disease indication and outcomes, may become more common in the future.  This idea is still new but gaining traction.

Treatment centers providing CAR T-Cell Therapy may already be participating in the PULSE + Plus™ transplant program as a center of excellence allowing the opportunity for single case negotiations by leveraging existing contractual relationships and pricing.  Access to negotiated single case CAR T-Cell Therapy pricing through PULSE + Plus™ by contacting your PULSE clinician to initiate the referral process and obtain a negotiated single case rate. Until more volumes are seen to establish clinical and financial outcomes data, there will not be a structured network offering for CAR T –Cell Therapy treatment by PULSE + Plus™, but single case negotiations will be provided

Even with negotiated single case CAR T–Cell Therapy rates, inappropriate billing practices and errors, significant inflation of charge and non-covered services could result in excessive claim payments. Negotiated contract terms should be applied to correctly billed charges and using discounts alone is not an effective strategy to mitigate risk. Ensuring claim payment integrity either prospectively or retrospectively is a necessity even though it can be challenging due to the complexity and high level of detail inherent in hospital and physician claims.

PULSE + Plus™,  applies an effective review of these claims required to make certain that the coding and regulatory compliance as well as clinical outcomes are in line with the claim payment. Our successful resolution of the review findings with hospital and physician providers is an important detail to highlight as this process requires a special skill set to address the discoveries as well as time to come to an agreement.

In summary, when evaluating costs for medical technologies like CAR T– Cell Therapy, it is important to weigh the overall value versus dollar figures and assess the probability of a high likelihood of cure or favorable quality-adjusted life years. In the case of the recent approval of CAR-T-Cell Therapy for pediatric leukemia, the therapy yields a high likelihood of cure therefore, the value equation is favorable. As with all complex diagnoses, PULSE + Plus™ is ready and able to help our clients in obtaining the best possible financial and clinical outcomes.

 

Contact the experts at the PULSE + Plus™ team online, by phone at 415-354-1551 or by email.


[1] http://blog.dana-farber.org/insight/2016/06/why-does-cancer-risk-increase-as-we-get-older/Cencer
[2] https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
[3] http://www.bloodjournal.org/content/124/2/188?sso-checked=true
[4] https://www.consumerreports.org/drug-prices/kymriah-first-gene-therapy-costs-475000-dollars-childhood-cancer/
[5] https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm581216.htm

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