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Insights and future perspectives of CAR T-Cell therapy

Evolving Oncology Landscape

The advances in cancer treatment for the past 20 years are very encouraging. Antitumor therapies, such as radiation, chemotherapy, and surgery, not only have short-term curative effects but can also cause serious side effects that affect a patient's quality of life (QOL).
Immune-based therapies, such as cancer vaccines, engineered immune cells, and checkpoint inhibitors, help patient's immune system distinguish cancer cells from normal cells and destroy them. Historically, these therapies have seen massive developments, with the potential to induce sustained remissions in patients with refractory cancer.1,2
Lately, adoptive cell therapies (ACTs) have shown great potential in cancer treatment. These therapies separate immunocompetent cells via leukapheresis, which are then reengineered to eliminate cancer cells directly or by stimulating body's own immune response.2
For the past few years, among the ACTs, chimeric antigen receptor (CAR) T-cell therapy is novel and evolves to be a game changer in the field of cancer treatment. At present, there are many clinical trials that are evaluating CAR T-cell therapies on a global scale in both hematologic malignancies and solid tumors, and they have shown promising outcomes. CAR T-cell therapy has been successful in hematologic cancers; however, it faces many challenges in clinical and commercial translation.1,3
Indegene Oncology Centre of Excellence (COE) experts have analyzed the oncology landscape and put together a comprehensive white paper to help business and medical teams with detailed insights into the CAR T-cell therapy space. This white paper can help healthcare organizations better position their products through the patient journey and competition by considering the existing and potential upcoming challenges with a futuristic outlook.

Implications on Cell Therapy

The year 2020 saw major external disruptions to cell therapy development and commercialization because of the Covid-19 pandemic, which directly impacted many anticipated 2020 milestones across the cell therapy landscape (Table 1).4
However, there were numerous positive developments toward a promising future that addresses some key questions on the development of cell therapies4:
CAR T-cell manufacturing: Improvement in autologous CAR T-cell design and manufacturing is at the forefront, especially, on the question of autologous versus allogeneic cell source. Allogeneic CAR T-cell manufacturing has several advantages over autologous CAR T cells in terms of speed, cost, and so on. But the question whether they will match the efficacy of the autologous CAR T cells remains unanswered
Successfully launched for the treatment of hematological malignancies. However, research that evaluates their efficacy in the treatment of solid tumors is ongoing
Use of enzymatic (non-viral) approaches for genetic modification of T cells such as CRISPR editing or Sleeping Beauty
Table 1. Major Developments in Cell Therapies: Pre-2020 and During 2020
FDA Approved (pre-2020) Significant Clinical Data/Regulatory Progress in 2020Newly Entering Clinic and/or No Major 2020 Updates
Cell typeT cellNK cellDC vaccine
Cell sourceAutologous patient-derivedDonor derived allogeneiciPSC-derived allogeneic (stem cell-based)
Antigen targeting approach
CAR (cell surface targets only)
None (cell expansion only)
TCR (MHC-presented targets only)Primed (exposed to target antigens)
Other modificationsActivity boosting (e.g., costimulatory)Safety editing (e.g., TCR deletion)
Dual targeting
Activation/Safety switches
Genetic modification methodViral vectorsEndonuclease enzymes (e.g., CRISPR)Transposons (e.g., Sleeping Beauty)
CAR, chimeric antigen receptor; CRISPR, clustered regularly interspaced short palindromic repeat; DC, dendritic cell; iPSC, induced pluripotent stem cell; MHC, major histocompatibility complex; NK, natural killer; TCR, T-cell receptor.

Engineering Immune Cells to Treat Cancer

CAR T-cell therapy involves a patient's T cells (patient's own or a donor's immune system cell) to express a CAR targeting a specific tumor antigen.5 CAR T-cells are made by removing healthy T cells from either the blood of a patient (autologous) or a donor (allogeneic) and genetically modifying them to express a CAR that is specific to a selected tumor cell surface protein (e.g., CD19 in leukemias) (Figure 1). The CAR T-cells are then infused back into the patient's bloodstream to circulate throughout the body to find and kill cells expressing the CAR T-cell target antigen.
Figure 1. Key components of CAR T cell therapy. CAR, chimeric antigen receptor.
 Figure 1. Key components of CAR T cell therapy. CAR, chimeric antigen receptor.

CAR Construct

Chimeric antigen receptors (CARs):
These are synthetic proteins composed of 2 main regions (Figure 2), an extracellular domain that recognizes proteins on tumor cells and an intracellular domain that activates the T cell via signaling once the antigen is bound.6
Tumor-recognition domain:
This portion is exposed to the outside via the ectodomain part of the CAR. It identifies and interacts with target antigens and attaches itself to tumor cells that express matching proteins. This domain is composed of variable regions of a monoclonal antibody linked together as a single-chain variable fragment (scFv).7
Spacer:
This is also known as a hinge region. It is present between the recognition domain and the transmembrane domain. The main objective of the spacer is to enhance the flexibility of the scFv receptor head and decrease the spatial constraints between the CAR and the target protein. This promotes binding of the antigen between the CAR T-cells and the target protein.7
Transmembrane domain:
This helps to anchor the CAR to the plasma membrane and acts like a bridge between the extracellular portion and the antigen recognition domains along with the intracellular signaling region.7
T-cell activation domains:
This domain lies in the endodomain part of the CAR. After an antigen is targeted, the receptors group together and transmit an activation signal, which is then perpetuated within the T cell.7
Figure 2. Structure of CAR receptor
Figure 2. Structure of CAR receptor

Engineering Strategies in CAR Structure

The structural design of CAR has evolved substantially over the years.8,9
First-generation CARs contain the CD3ζ chain domain as the intracellular signaling domain along with an extracellular domain, a spacer region, a transmembrane portion, and ≥1 signaling domains
Second-generation CARs have an added co‐stimulatory domain, such as CD28 or 4‐1BB, to enhance T-cell proliferation, resistance to apoptosis, in vivo persistence, and cytokine secretion
Third-generation CARs have many co-stimulatory domains, such as CD28-41BB or CD28-OX40, to augment T-cell activity. Studies have shown that effector functions and in vivo persistence are improved
Fourth-generation CARs are based on second-generation CARs (containing 1–3 ITAMs) paired with a constitutively or inducibly expressed chemokine (e.g., IL-12)
Fifth, or 'next generation', is also based on the second generation of CARs, with the addition of intracellular domains of cytokine receptors (e.g., IL-2Rβ chain fragment)

Patient Journey

Figure 3. Typical CAR T-cell patient journey. 10
 Figure 3. Typical CAR T-cell patient journey.
At present, there are 2 main sources of T cells that can be engineered into CAR T-cells: those derived from a patient (autologous) and those derived from a healthy donor (allogeneic). Here is how both the therapies differ.

Autologous CAR T-Cell Therapy

A patient must consult a physician specialist (an expert in administering and managing CAR T-cell therapy
The patient will then undergo multiple evaluations to see if they have a cancer type that is eligible for the treatment with CAR T-cells and if the overall medical condition is good enough to go through with CAR T-cell treatment
The patient will then have their white blood cells (WBCs) collected through a process called leukapheresis
After this, CAR T-cells are manufactured in a laboratory. This would take around 3 to 4 weeks depending on the type of technology used
During this period, the patient is monitored to see if they need any additional treatment known as bridge therapy
Once the CAR T-cells are manufactured, the patients are given a lymphodepletion chemotherapy, which is administered to change the immune environment in the body so the CAR T-cells are able to stay alive and be active against the tumor when infused
The patient then receives the CAR T-cells via intravenous (IV) infusion. The patient is closely monitored by the physician for the next 4 to 6 weeks
As CAR T-cell therapy is an immunotherapy, there are certain side effects involved, such as cytokine release syndrome (CRS) and neurologic symptoms. The patient needs to be monitored in the hospital during this time frame and might also need ICU-level care
There is a need for a multidisciplinary team of experts, which includes not only oncologists but also an ICU team, neurologists, cardiologists, infectious disease specialists, and so on, to support the patient during this treatment period

Allogeneic CAR T-Cell Therapy

The T cells are derived from a healthy donor (unlike autologous CAR T-cell therapy) and the CAR T-cells are developed from a single manufacturing batch, with the potential to benefit multiple patients. Hence, they are known as “off-the-shelf” CAR T-cells
The patients would receive the CAR T-cells via IV infusion and be closely monitored by the physician for side effects, such as graft versus host disease (GvHD)
As there are not any approved allogeneic CAR T-cell therapies till date, the exact timeline for monitoring these events is unknown

CAR T-Cell Manufacturing Process Is Complex

Manufacturing CAR T cells is a highly complex process, which requires collecting T cells and genetically modifying them to express a transgene encoding a tumour-specific CAR and infusing the CAR T cells into the patient.

Autologous CAR T-Cell therapy

Figure 4. Process flow for autologous CAR T-cell therapy.
Figure 4. Process flow for autologous CAR T-cell therapy.
Patient's WBCs are collected through a process called leukapheresis. During this process, the WBCs are separated from the collected blood and the remainder is returned back to circulation
In the manufacturing steps, the viral vector is the main raw material for the transduction of the CAR into the T cells of the CAR T-cell manufacturing process
During the activation process, the T cells are incubated with the viral vector that encodes the CAR. During incubation, the viral vector attaches to the patient cells and, upon entry, introduces its genetic material, RNA, into the patient cells. After few days, the vector is washed out.
In CAR T-cell, this genetic material encodes the CAR. The RNA is reverse transcribed into DNA, which is then integrated into the genome of the patient cells permanently
Therefore, the expression of CAR is maintained as the cells divide and grow in large numbers
Retroviruses are commonly used in gene therapy, but they are incapable of infecting non-dividing cells. Therefore, lentiviruses are used because they can transduce non-dividing cells11
Figure 5. Process flow for allogeneic CAR T-cell therapy.
Figure 5. Process flow for allogeneic CAR T-cell therapy.

Allogeneic CAR-T Therapy:

The manufacturing process12 for allogeneic CAR T-cell products starts with a source of third-party healthy T lymphocytes collected by leukapheresis
Technologies such as viral vector-mediated transgenesis or gene knock-in mediated by gene editing enable the permanent insertion of recombinant DNA that encodes CAR
T cells are then expanded using anti-CD3/anti-CD28 beads and cytokines
The allogeneic CAR T-cells are then filled in vials
The product is then stored, frozen, and shipped to hospitals when needed12

Challenges With CAR T-Cell Therapy

Companies with breakthrough CAR T-cell therapies not only focus on the science involved in the development but also give equal emphasis on how to bring these therapies into the market. Unlike conventional treatments, the entire process from manufacturing through sales and marketing is not clearly defined in cell and gene therapies.13

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
Malignant contamination:
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
T-cell variability:
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
T-cell dysfunction:
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:
Outpatient:
For patients undergoing CAR T-cell therapies, Medicare reimburses at a level commensurate with what the companies have been charging
Inpatient:
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
6. Pricing
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

Allogeneic CAR T-Cell Therapy

One of the biggest risks involved in the treatment with allogeneic therapies is the development of GvHD. This occurs when the TCRαβ receptor on the infused allogeneic CAR T-cells recognizes cell surface Human Leukocyte Antigen (HLA) class I and class II molecules on the recipient's cells as "non-self," which elicits an unwanted systemic immune response. As a result, the patient is given stronger dose of drugs to avoid this complication. These medications are strong immune suppressants and dosing regimens could pose a challenge. It could also take a toll on the patient's overall condition.17
Owing to these immunosuppressants, the patient could be more susceptible to infections, which, if occurs, may require further medications to treat them and the infections could become more severe over a period of time.18
Gene-editing technologies, such as CRISPR and TALEN, are popular among allogeneic therapies. However, the fact that there is not a long success track record in humans to confirm the safety of these technologies is also a challenge. Alteration of genome adds another layer of risk for which we may be unaware of methods to evaluate it.18

Sources for Allogeneic CAR T-Cell Therapy

During the manufacturing of CAR T-cells, the T cells are usually derived from peripheral blood mononuclear cells (PBMCs) and very rarely from umbilical cord blood (UCB).
Peripheral blood mononuclear cells (PBMCs):
Allogeneic CAR T-cells manufactured from PBMCs provide the ability to create multiple vials from 1 apheresis product, and because these are produced from healthy donors, the immune cells are not affected by immune effects of cancer or exposed to any chemotherapeutics agents, unlike autologous T cells derived from patients. To decrease the heterogeneity of the CAR T-cell therapy, the selection of donors is the key factor in the process
Umbilical cord blood (UCB):
Reduction in the incidence and severity of GvHD is observed when CAR T cells are derived from UCBs
Induced pluripotent stem cells (iPSCs) or embryonic stem cells:
In theory, induced pluripotent stem cells (iPSCs) have an unlimited capacity to self-renew and can be banked and used indefinitely. Another advantage is that CAR T-cells derived from iPSCs are homogenous, although the safety and efficacy of this approach are not yet confirmed20
The reason of choosing the right donor for developing allogeneic therapies is important because it reduces the risk of alloimmunization and, subsequently, the risk of GvHD.

Advantages of Allogeneic Therapy Over Autologous Therapy

Besides clinical aspects, allogeneic therapies can provide improvement to the manufacturing part of the equation, such as the shift from an adherent to a suspension manufacturing archetype
Time and quality control:
As the product is manufactured ahead of time, it can be manufactured at a large scale and have sufficient time for quality checks and undergo tests for safety and potency. It can be cryopreserved until needed by a patient. As a result, the "vein-to-vein" time is drastically reduced and the product can be timely available for the patient13
Availability of T cells:
The availability of T cells is the most important precursor material in the manufacturing process and a determinant of the success of the therapy. Low-quality T cells in a patient suggest a good reason to try an allogeneic product17
Low cost:
Another benefit to both the industry and the patient is the perception that allogeneic CAR T-cell products will be less expensive. However, data supporting these assumptions are yet to be confirmed. It is yet to be analyzed whether the cost of treatment with allogeneic therapies will be shared by both the patient and the manufacturer13,17
Avoidance of other issues related to autologous CAR T-cell therapies:
Harvesting, product variability and T-cell dysfunction are some of the issues related to autologous CAR T-cell therapies. Having an alternative source of CAR T-cells could expand treatment to additional patients, such as those with low T-cell levels, those who have harvest failures, or those who need treatment before autologous CAR T-cells can be manufactured13 A survey by InCrowd involving hematologists and oncologists revealed that 65% of respondents expressed the most excitement for autologous CAR T-cell therapies, whereas 60% viewed allogeneic CAR T-cell therapies as having the same level of promise.
Although these therapies generated similar levels of excitement among clinicians, fewer than half of the respondents (45%) indicated that they were very or extremely familiar with allogeneic CAR T-cell therapies compared with the degree of familiarity expressed by 65% of the respondents who received autologous CAR T-cell therapies.
Till date, the FDA has approved only autologous CAR T cell therapies. Nevertheless, there is evidence that off-the-shelf CAR T-cell therapy is a potentially more accessible and cost-effective alternative to the time-consuming personally engineered process required by autologous therapies.
According to Stephan A. Grupp, MD, PhD, Director of the Cancer Immunotherapy Program at Children's Hospital of Philadelphia, the number of patients successfully treated with allogeneic cell therapies in clinical trials is relatively small. There is still a lot to learn on how well these therapies work.
The efficacy data for allogeneic therapies are very limited. Furthermore, it remains unclear how long the therapies will last within the body, which is another aspect of ongoing investigation for both autologous and allogeneic cell therapies.
Access to off-the-shelf therapies is limited to clinical trials and none of the currently being tested therapies are close to FDA approval. The goal is to have an FDA-approved product, but this is yet to be achieved.19
Anticipated Benefits of Allogeneic Versus Autologous CAR T-Cell Therapies
More convenient
Greater accessibility and availability
Lower cost

Advancements in Treatment Options

The current phase 2 and phase 3 trials involving CAR T-cell therapies are majorly autologous. At present, there are not any allogeneic CAR T-cell trials in mid-/late-stage development.20
Allogeneic CAR T-cell space is new and still being explored. There are certain severe risks involved with allogeneic therapies such as GvHD. Hence, new methods or gene-editing technologies to overcome these challenges are being studied. The number of allogeneic CAR T-cell trials is lower than that of autologous CAR T-cell trials and is expected to rise in the coming years, with new developments in this space.

Current CAR T-Cell Therapies in Clinical Development

CD19 and B-cell maturation antigen (BCMA) are popular targets in late-stage trials (phase 2/phase 3).20
Figure 6. Clinical development in CAR T-cell therapies by targets (updated till March 2021).
Figure 6. Clinical development in CAR T-cell therapies by targets (updated till March 2021).

CAR T-Cell Development by Tumor Type (Solid Tumor versus Hematologic Malignancies)

The majority of the clinical trials of CAR T-cell therapies are focused on hematologic malignancies. Solid tumors present a more difficult target compared with hematologic malignancies. All CAR T-cell clinical trials (phase 2 and phase 3) are focusing on hematologic malignancies.

Key Companies in This Space

Figure 8. Clinical development of CAR T-cell therapies by top companies (updated till March 2021—phase 2 and 3).20
Figure 8. Clinical development of CAR T-cell therapies by top companies (updated till March 2021—phase 2 and 3).
One of Gilead's key areas of focus in 2021 is to expand and advance key oncology therapies such as Yescarta in 2L diffuse large B-cell lymphoma (DLBCL). Tecartus is also being investigated in additional indications such as adult and pediatric acute lymphoblastic leukemia (ALL) (in phase 2 clinical trials)21,22
Novartis is also focused on indication expansions for Kymriah with expected submission planned in relapsed/refractory (RR) follicular lymphoma in 2021 (US/EU/JP) along with major data readouts from phase 3 RR DLBCL study23
BMS: On March 26, 2021, the FDA approved idecabtagene vicleucel (Abecma) for the treatment of adult patients with RR multiple myeloma after ≥4 prior lines of therapy. Ongoing studies of ide-cel include a phase 3 trial comparing ide-cel with the standard treatment in heavily pretreated patients (2-4 prior lines of therapy), a phase 2 trial of triple class-exposed and high-risk patients, a phase 1 trial of patients with high-risk newly diagnosed multiple myeloma, and an exploratory phase 1/2 trial of combination treatment in the RR setting24

Current Therapies

The CAR T-cell therapy market is currently dominated by Novartis' Kymriah (tisagenlecleucel), Gilead's Yescarta (axicabtagene ciloleucel) and Tecartus (brexucabtagene autoleucel),4 BMS/Juno's Breyanzi (lisocabtagene maraleucel),25 and BMS/Bluebird Bio's Abecma (idecabtagene vicleucel, BB-2121).24 They all target CD19 molecule except for Abecma, which targets the BCMA.
There is a huge opportunity if cell therapies can succeed in other targets and indications. This extends beyond BCMA in multiple myeloma, perhaps to include solid tumors too, where the T-cell receptor T cells (TCR-Ts) and tumor-infiltrating lymphocytes (TILs) could be approved by 2021 to 2022.

Filings and Approvals Expected in the Near Term

For the next few months, a significant activity with expected filings and FDA decisions is anticipated, especially in the autologous CD19-directed (Table 2) and BCMA-directed CAR T-cell (Table 3) space. There are also additional data releases on the allogeneic CD19-directed CAR T cells, which provide evidence if the allogeneic approaches can supplant the established autologous CAR T-cell therapies.4
Table 2. CD19-Directed CAR T-Cell Therapies
Table 2. CD19-Directed CAR T-Cell Therapies
Table 3. BCMA-Directed CAR T-Cell Therapies
 Table 3. BCMA-Directed CAR T-Cell Therapies
Other BCMA-Targeting CAR T cells: Arcellx's CART-ddBCMA (BCMA-specific CAR-modified T-cell therapy) elicited 100% ORR in relapsed/refractory multiple myeloma in a phase 1 study (data presented at ASCO 2021).32
Figure 9. "Next-Generation" CAR T-Cell Therapies 4
Figure 9. "Next-Generation" CAR T-Cell Therapiess

Future Outlook for CAR T-Cell Therapy

In the past decade, cell therapy has established itself as a "fourth arm" in the treatment of cancer, complementing other traditional treatments such as surgery and radiation. Researchers who have worked in the development of CAR T-cell therapy believe that the next decade could yield much better results.35
The following challenges remain to be addressed in the future:
The most formidable being the effective adoption of cellular therapy beyond blood cancers, because solid tumors account for 90% of cancer deaths
Another major challenge would be to reduce the cost. The price for the first 4 approved CAR T-cell therapies ranges from $373,000 to $475,000. Also, added hospitalization and office visits costs range between $23,500 and $53,000
Making CAR T-cell treatment safer: This will directly reduce outpatient administration and help reduce treatment costs
Change from 6-month course of therapy for B-cell malignancies into a one-time infusion of cells: This will allow patients to resume normal life activities after a month
Improving treatment durability is a major challenge: A better understanding of the mechanisms behind antigen escape could lead to more durable therapies and actual cures. CAR T-cell therapy is likely to be used as a first-line therapy for at least B-cell lymphomas in the future
Researchers believe scalable, allogeneic or CAR-NK options will help reduce cost in the next decade. Along with costs, an efficacy better than/comparable with that of the current standard of care (SOC) is desired
The future for CAR T-cell therapy is bright, because there is a great amount of enthusiasm about using the body's own immune defenses to treat cancer35
The year 2021 is anticipated to be an even richer source of new data and decisions that will further characterize the ultimate potential of cell therapies.4
CD19-directed CAR T-cells
Questions That Would Be Answered:
How will the autologous CD19 CAR-T space evolve, with ongoing expansions of Gilead’s Yescarta/Tecartus and Novartis’ Kymriah, and BMS/Celgene’s liso-cel entry?
How will allogeneic or next-generation autologous competitors compare?
BCMA-directed CAR T-cells
Key Questions in BCMA
How will the BMS/Celgene’s ide-cel (idecabtagene vicleucel, Abecma) and Janssen’s cilta-cel (ciltacabtagene autoleucel, formerly JNJ-68284528) competition shake out, as well as these versus out-of-class BCMA-targeted therapies?
The expansion of the marketed/late-stage autologous CD19 CAR T cells into other tumor types/earlier lines and their future competition. We need to wait and watch if the combinations unlock further efficacy.4
Future Outlook for CAR T-Cell Therapy
Expected launch of BCMA-directed CAR T-cell therapy. Comparison of next-generation autologous and allogeneic, and with reference to out-of-class BCMA competition4
Future Outlook for CAR T-Cell Therapy

Conclusion

Immunotherapies, such as checkpoint inhibitors, are successful in cancer treatment and work by inhibiting a mechanism that tumor cells use to hide from immune cells. CAR T-cell therapies go a step further to enhance the natural immune system against a specific tumor antigen by engineering the T cells.46
Since the approval of the first CAR T-cell therapy in 2017, widespread research, proliferating clinical trials, aggressive mergers and acquisitions (M&A) activity, and lucrative IPOs have created a robust CAR T-cell market. The massive influx of intellect, resources, and capital is driven by the success of axicabtagene ciloleucel (Yescarta) for relapsed or refractory large B-cell lymphoma; tisagenlecleucel (Kymriah) for relapsed or refractory large B-cell lymphoma, and B-cell precursor ALL in patients up to 25 years of age; brexucabtagene autoleucel (Tecartus) for relapsed or refractory mantle cell lymphoma, idecabtagene vicleucel (Abecma) for adult patients with relapsed or refractory multiple myeloma after ≥4 prior lines of therapy; and lisocabtagene maraleucel (Breyanzi) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after ≥2 lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.25,47
More than 600 CAR T cell therapy trials are active worldwide, and the FDA is processing >900 investigational new drug applications for cell and gene therapies, including for hematologic malignancies and solid tumors, according to a presentation at the American Society of Clinical Oncology annual meeting.47
Although there were delays and setbacks in 2020 because of Covid-19, namely clinical trial delays and manufacturing issues (which in turn led to regulatory delays), overall, the field has made significant progress. It has set the stage for an eventful 2021 to 2022 where multiple approvals are expected in new targets with the BCMA-directed CAR T cell(s).
In addition, we expect to see data from the numerous phase 1 trials that are continuing to enroll, which will answer questions not just about targets and indications but about the attributes of allogeneic cell sources, NK cell-based therapies, and various modifications and modification methods (eg, CRISPR based).
Finally, these data releases and regulatory advancements will further clarify the ultimate potential for cell therapies within the oncology market, including out-of-class competition.4

Abbreviations

ACT: Adoptive Cell Therapy
ALL: Acute Lymphoblastic Leukemia
ASCO: American Society of Clinical Oncology
BCMA: B-Cell Maturation Antigen
Blenrep: Belantamab Mafodotin
CAR: Chimeric Antigen Receptor
Cilta-cel: Ciltacabtagene Autoleucel
CLL: Chronic lymphocytic leukemia
CR: Complete Response
CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats
DLBCL: Diffuse Large B-cell lymphoma
EHA: European Hematology Association
FDA: Food and Drug Administration
FL: Follicular Lymphoma
GvHD: Graft Versus Host Disease
IBCL: Indolent B-Cell Non-Hodgkin lymphoma
ICH: The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use
ICU: Intensive Care Unit
Ide-cel: Idecabtagene Vicleucel
IL: Interleukin
IPO: Initial Public Offering
LBCL: Large B-Cell Lymphoma
Liso-cel: Lisocabtagene Maraleucel
MM: Multiple Myeloma
MZL: Marginal Zone Lymphoma
NHL: Non-Hodgkin Lymphoma
NK: cells Natural Killer cells
ORR: Overall response rate
RMAT: Regenerative Medicine Advanced Therapy
RR: Relapsed or Refractory
WBC: White Blood Cell

References

1.
CAR T-Cell Therapy: A Game Changer in Cancer Treatment. Accessed December 05, 2020.  https://www.hindawi.com/journals/jir/2016/5474602/
2.
CAR-T Cell Therapy in Cancer: Tribulations and Road Ahead. Accessed December 05, 2020.  https://www.hindawi.com/journals/jir/2020/1924379/.
3.
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