Autologous CAR T-Cell Therapy
1. Commercialization Hurdles
Longer manufacturing time:
The time required for manufacturing autologous CAR Tcells is approximately 1 month. During this period, patients would be waiting in anticipation for the treatment. As most of the patients are in the relapsed and refractory stages, the wait time could risk their condition and their condition may eventually deteriorate
Need for interim therapies:
During the CAR T-cell manufacturing wait time, the patients may require additional treatment (bridging therapy) to stabilize their condition
The end product after the leukapheresis process may contain malignant cells that could result in transduction with the CAR protein, resulting in the escape of the contaminating cells from being eliminated by CAR T-cells. The risk of this occurrence majorly depends on the type of disease and timing of cell harvest
There is also a chance of patient‐specific variation in T-cell phenotype and prevalence, which may result in different expansion and persistence of cell products. Reasons for such variability could be age, disease, previous lines of treatment, and interpatient heterogeneity
Insufficient T-cell expansion:
Patients receiving CAR T-cell therapies may have previously undergone multiple chemotherapies because of which the amount of T cells required for manufacuring CAR T cells may be insufficient and the patients may be lymphopenic
The T cells of the patients may also be dysfunctional as a consequence of the disease burden or being heavily pretreated with other therapies. Owing to this, the T cells could not be viable enough to act as a drug delivery vehicle for the CAR T-cell therapies
Limited opportunity for redosing:
The CAR T-cell therapies are produced in a limited amount during 1 batch of manufacturing, and, therefore, patients may not be able to receive a second dose, if needed, quickly enough because of the longer manufacturing time13,14
2. Patient Adverse Events, Restricted Patient Segment, and Vein-to-Vein Time
Once the CAR T-cell therapy is initiated, the patients are monitored for adverse events such as CRS and neurologic symptoms. These side effects could be severe and the patients might need ICU-level care. Although these side effects are expected as a result of the CAR T-cell treatment, they could deteriorate patients' overall condition.
The patient segment receiving the treatment is quite restricted. The patients who receive these therapies are those in RR setting, who are heavily pretreated, and may have failed to improve with prior therapies.
The "vein-to-vein" time can be critical to the patients and is defined as the time between apheresis and delivery of the CAR T-cell product to the clinic or hospital. Owing to the rapid progression of disease, the vein-to-vein time could have a negative impact on the patients.13,15
3. Clinician Awareness and Willingness
In spite of significant potential, the degree to which oncologists would refer patients to CAR T-cell therapy is still unknown. CAR T-cell certified healthcare professionals (HCPs) under Risk Evaluation and Mitigation Strategies (REMS) guidelines should mandatorily treat patients. However, some physicians are hesitant about prescribing CAR T cells, because they are not sure about its placement in the treatment algorithm and its impact on further lines of therapy.
4. Extensive Documentation
There are certain communication and guidance documentations that are required to be maintained by the company that manufactures the CAR T-cell product. Each step has to be documented for regulatory purposes. Manufacturing requires “more than minimal manipulations” (MTMMs) on the cell product, and there are certain US- and ICH-specific guidelines relevant to the development of CAR T-cell therapies. If any such documentation goes missing during filing to regulatory authorities, the US Food and Drug Administration (FDA) can reject the Biologics License Application (BLA) application.15
5. Patient Access and Reimbursement
Although this personalized treatment approach has gained popularity, it has been a significant challenge for healthcare providers, payers, and insurers, thereby creating barriers to patient access.
Medicare has 2 approaches for reimbursement:
For patients undergoing CAR T-cell therapies, Medicare reimburses at a level commensurate with what the companies have been charging
Medicare covers 65% of what the companies are charging
In inpatient setting, the losses that hospitals incur providing CAR T-cell therapies are unsustainable and may limit the number of hospitals that are willing to offer CAR T-cell therapies, affecting patient access to CAR T-cell therapy.13
Pricing is a major barrier to patient access. With >$400,000 per patient, these therapies are very expensive, and the complex personalized manufacturing process and the need for highly skilled staff significantly add to the cost.
The cost of therapy is only a portion of the total cost of the treatment. After treatment, many patients suffer significant adverse events that necessitate intensive and inpatient care for several days, adding to the treatment cost.13-16
7. Expansion to Other Indications
Solid tumors are presented with a more difficult target in the treatment by CAR T-cell therapies. Identification of suitable antigens in solid tumors is challenging because such antigens must be highly expressed on the majority of the cancer cells for the CAR T-cells to target but must be absent on the normal tissues.
CAR T cells are not efficiently transported into the center of the solid tumor masses because of which the hostile tumor microenvironment may suppress the T-cell activity. Hence, the trials for solid tumors are less dominated by CAR T-cells, and majority of these trials target blood cancers. CAR T-cell therapies account for more than half of all trials for hematologic malignancies.13