Chimeric antigen receptor (CAR) T cell therapy is a form of T-cell therapy in which T cells are genetically engineered to express a CAR. CAR T cells preparation begins with obtaining a blood sample from the patient. The collected T cells are sent to a laboratory where they are genetically modified, with the use of an inactive virus, to produce specific proteins, chimeric antigen receptors (CARs) on their surface. The CARs are important because they enable the T cells to recognize and bind to specific antigen proteins expressed on the surface of the patient’s cancerous cells. Once infused, CAR T cells circulate throughout the patient’s body, and attach to cancer cells. This binding action stimulates an immune attack and destruction of the cancer cells through release of cytokines and cytotoxic molecules including granzymes and perforins.
Several CAR T cell therapy agents are currently approved for the treatment of relapsed or refractory liquid tumors that affect less than 5% of cancer patients today1. The different agents utilize slightly different methods of genetic engineering to transform the patient’s T cells into CAR-T cells. The pipeline of investigative CAR T-cell therapies has rapidly expanded to more than 500 trials underway in 20212. The first generation of autologous CAR T targeted CD19, a protein found on the surface of most normal and malignant B cells, in B cell cancers. However, clinical programs today span a wider range of targets and tumor types.
Four products have been approved so far for CD-19 targeted CARTs: Kymriah (tisagenlecleucel, Novartis) approved in August 2017 for the treatment of patients up to 25 years of age with R/R acute lymphoblastic leukemia (ALL), and in May 2018 for adults with R/R diffuse large B-cell lymphoma (DLBCL). Yescarta (axicabtagene ciloleucel, Kite Pharma / Gilead Sciences) approved in October 2017 for the treatment of adults with R/R DLBCL and in March 2021 for R/R Follicular Lymphoma. Tecartus (brexucabtagene autoleucel, Kite Pharma / Gilead Sciences) approved in August 2020 for patients with R/R mantle cell lymphoma. Breyanzi (lisocabtagene maraleucel, Bristol-Myers Squibb) approved in February 2021 for the treatment of adult patients with R/R DLBCL.
Additional CAR Ts target B-cell maturation antigen (BCMA), a common cell surface antigen in multiple myeloma as well as a number of other cell surface targets. In March 2021, Abecma (idecabtagene vicleucel, Bristol-Myers Squibb / Bluebird Bio) became the first BCMA directed CART therapy approved for R/R Multiple Myeloma.
Challenges to commercialization of CAR T Cell Therapies
Despite the strong efficacy data in clinical trials, there are three key challenges affecting the commercialization of CAR Ts: complex manufacturing and supply chain, high-cost commercial model, and reimbursement challenges.
All CAR T-cell therapies on the market and a majority of clinical assets are autologous, resulting in costly manufacturing and supply chain. There are limited economies of scale and high cost of goods sold due to shortage of manufacturing slots. Moreover, transportation of CART requires a complex cold chain, and the management of chain of custody and chain of identity of CAR T is critical.
In the United States, only a limited number of certified academic medical centers (AMCs) offer commercial CAR T, often requiring patients to travel long distances. One of the main reasons for the limited number of commercial sites is the laborious site setup process—which involves extensive preparation and certification to offer CAR T. Nearly all CAR T treatments are provided in inpatient settings at AMCs. While this highly concentrated expertise allows for close monitoring of adverse events including Cytokine Release Syndrome (CRS), it also is extremely cumbersome for patients who often need to travel multiple times (for diagnosis, apheresis, or transfusion) with an advanced-stage cancer.
Regarding reimbursement, in the inpatient setting, the current diagnosis-related group payment is insufficient to cover the cost of CAR T care. Even with the outlier and new technology add-on payments (NTAP), hospitals have stated that they are expected to take a net loss on Medicare patients treated with CAR T. In the outpatient setting, Medicare Part B would reimburse using the ASP plus model, which would ensure cost recovery for providers. New CAR T therapies including BCMA CAR Ts and select CD19 CAR Ts are being evaluated to determine if their safety profile is suitable to administer in an outpatient setting3. Commercial payers currently approve CAR T on a case-by-case basis with payer-specific justification documents.
To solve these challenges, innovative contracting mechanisms are starting to be considered, including outcomes-based contracting. Given the uncertainty of long-term response durability, it is important for manufacturers to continue generating evidence to support the value of CAR T for patients.
Next-generation CAR T-cell Therapy Treatments
New autologous CAR T-cell therapies treatments are being investigated for solid tumors and NHL. So far, this goal has been elusive— analysis of all solid-tumor CAR Ts tested in humans revealed a mere 4% complete response rate.
Allogeneic derived chimeric antigen receptor (CAR) cell use T cells from a non-related healthy donor rather than the patient themselves, and may have several advantages, including, the potential to be manufactured in advance and stored for off-the-shelf for immediate use, low cost of treatment, a simplified supply chain, and reduced product variability. Having this alternative source of CAR T cells could expand treatment to additional patients, such as those with low T-cell levels, harvest failures, or those who need treatment before autologous CAR T cells can be manufactured. Clinical testing is already underway, as it is critical to validate lack of graft-versus-host disease and clearance of allogeneic cells.
Fate Therapeutics and Allogene are leading the way in developing allogenic “off the shelf” CAR T cell therapies and their progress was updated at the ASH 2020 annual meeting.
Allogene’s AlloCAR T therapy uses T cells from healthy donors which are isolated in a manufacturing facility, engineered to express CARs to recognize and destroy cancer cells, and modified via gene editing to limit autoimmune response when given to a patient. These therapies are then stored for off-the-shelf use on demand. Allogene’s products are currently in Phase I-II clinical trials – Anti-CD19 allogeneic CAR T cells for adults with R/R NHL, and BCMA allogeneic CAR T cells for adults with R/R Multiple Myeloma.
Fate Therapeutics obtained IND for its iPSC derived allogeneic CART cell therapy FT819 in 2020. The process of creating FT819 begins with human induced pluripotent stem cells (iPSCs) that can differentiate into more than 200 types of human cells. The iPSCs are genetically engineered; a single clone is selected and multiplied in the laboratory to create a master engineered cell line that can be repeatedly used to generate cancer-fighting immune-system cells such as NK and T cells. The company plans to initiate clinical trials of FT819 for treatment of patients with R/R B cell malignancies, including CLL, ALL and NHL.
Manufacturers that make smart investments in allogeneic CARTs can drastically increase the number of patients they serve as well as the success rates of their treatments.
Sources:
- SEER Research Data: seer.cancer.gov
- clinicaltrials.gov
- Healthaffairs.org: Health Policy Brief, Medicare Part B