CAR T-cell therapy: Targeting cancer cell antigens with genetically altered T cells

Immunotherapy is one of the most exciting and promising new developments in cancer treatment. By taking advantage of the patient’s immune system to attack tumors, immunotherapy provides a more targeted approach than conventional therapies. One of the most exciting new immunotherapies is CAR T-cell therapy, an approach that has only been on the market for five years but has generated considerable (well deserved) publicity and interest in ongoing R&D efforts. This article first provides a brief overview of how CAR T-cell technology works, then summarizes currently approved drugs and next-generation approaches undergoing clinical trials, before discussing the market forecast and ending with the challenges and opportunities associated with CAR T-cell therapy.

How does CAR T-cell therapy work?

Chimeric antigen receptor (CAR) T-cell therapy is a novel gene therapy in which a patient’s immune cells (T cells) are programmed to fight against a specific antigen. Briefly, T cells are withdrawn from the patient’s blood, and CAR-based genes are altered in those cells. The mechanism is disease-dependent and personalized, as every disease and antigen is different. Finally, genetically modified CAR T cells are infused into the patient’s body. Once the CAR T cells start binding with the antigen, they proliferate and destroy more antigens present in the blood.

CAR construct:

A CAR is a synthetic construct consisting of three domains: extracellular, transmembrane, and intracellular. The extracellular domain, also called a single-chain variable fragment (scFv) recognition domain, can bind to the target cell surface antigens. It is connected via the transmembrane domain to the intracellular domain, which can trigger cellular signaling pathways to induce T-cell activation. The CAR T-cell domain constructs used are rapidly advancing. 

Image: Incorporating costimulation into CAR design.
Source: A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains.

All FDA-approved treatments and most clinical trials target CD19 or BCMA antigens, antigens present on the surface of B cells, but newer approaches are targeting different or multiple antigens. All first-generation constructs included an intracellular T-cell activation domain (CD3ζ), but researchers have developed second-generation constructs via the addition of CD28 or 4-1BB costimulatory domains between the transmembrane domain and existing intracellular domain (CD3ζ). Now, third-generation constructs are being developed by adding both CD137 and 4-1BB costimulatory domains, with the goal of increasing antitumor efficacy while also limiting severe adverse events.

FDA-approved CAR T-cell therapies:

A total of six CAR T-cell therapies are approved by the FDA, all for the treatment of blood cancers including lymphomas, leukemias, and multiple myeloma. These therapies are indicated when other treatments fail to work.

Abbreviations: AA, Accelerated Approval; ALL, acute lymphoblastic leukemia; BT, Breakthrough Therapy; MCL, mantle cell lymphoma; MM, multiple myeloma, OD, Orphan Drug; PR, Priority Review; r/r, relapsed or refractory; RMAT, Regenerative Medicine Advanced Therapy.

Technology progress in clinical trials:

Currently, more than 500 CAR T clinical trials are being conducted worldwide. These range from clinical trials that are still in progress for already approved products (Kymriah, Yescarta, Tecartus, and Breyanzi) to novel therapeutics. While early CAR T-cell therapies primarily targeted CD19, current clinical trials expand beyond CD19 to target a variety of antigens, including CD20, GD2, CD22, CD30, CD33, HER1, HER2, Meso, and EGFRVIII surface receptors. Ongoing trials span multiple populations, including pediatric, young adults, and high-risk patient groups. Interestingly, the majority of ongoing studies are being performed in East Asia (269 trials), followed by the United States (225 trials) and Europe (62), a trend that we address in more detail below.

Here, we summarize a few interesting novel approaches currently under clinical development:

Miltenyi Biomedicine:

Miltenyi Biomedicine is actively expanding its CAR clinical research program, which includes CAR T, CAR NK, and Adapter CAR approaches. Currently, several preclinical studies are ongoing for solid tumors, hematological malignancies, and relapsed or refractory diffuse large B cell lymphoma (DLBCL). The feasibility and safety data were very promising in the phase I trial of MB-CART2019.1 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Therefore, the company has moved for multi-center phase I/II clinical trials (NCT03870945).

The aim of this study is to evaluate the dosage, safety, toxicity, and efficacy of the drug MB-CART2019.1. In this novel treatment, the second-generation T-cell construct can express both anti-CD20 and CD19 immunoreceptors. This therapy has been selected for the priority medicines scheme (PRIME) in the European Union, and the company also filed an Investigational New Drug application for FDA approval. 

CRISPR Therapeutics AG:

CRISPR Therapeutics AG, a Swiss–American biotechnology company, has developed the unique T-cell product CTX110. This technique has shown promising results in an ongoing phase I single-arm, multi-center, open-label clinical trial (NCT04035434) for the treatment of relapsed or refractory B-cell malignancies. This CAR T-cell therapy targets CD19+ B-cell malignancies. The FDA has already granted regenerative medicine advanced therapy (RMAT) designation to CTX110, and the company has plans to expand trial registration, advance its immuno-oncology portfolio, and scale up its manufacturing capabilities.

venCell Therapeutics:

Blackstone Life Sciences, Intellia Therapeutics, and Cellex launched a new CAR T-cell company, AvenCell Therapeutics, whose goal is to combine CRISPR/Cas9 and CAR technology to launch universal CAR T-cell therapies for immuno-oncology and autoimmune diseases (UniCAR and RevCAR). Currently, the company is developing UniCAR, a switchable (turn on/off mechanism) universal CAR T platform with soluble adaptors against less differentially expressed antigens such as CD123 or PSMA in hematological malignancies and solid tumors. This technology is likely to enhance the efficacy and safety of CAR T-cell therapies. The recruitment for a phase I clinical trial (NCT04230265) using UniCAR-T-CD123 for the treatment of relapsed/refractory AML and UniCAR-T-PSMA directed against CRPC is ongoing. 

University Hospital of Heidelberg:

The University Hospital of Heidelberg is conducting an investigator-initiated trial on third-generation CD19-directed CAR T cells (NCT03676504). This unicenter phase I/II clinical trial is recruiting patients with a broad spectrum of relapsed or refractory haematologic malignancies including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and lymphoma (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma). This treatment will include pediatric patients, adults, and patients after allogeneic stem cell transplantation. The estimated study completion date is October 2023.

CAR T-cell market worldwide:

The global CAR T-cell therapy market has been estimated at over $5 billion, with the potential to grow at a compound annual growth rate (CAGR) of 19.7% through 2027.

Celgene Corporation, Kite Pharma, Autolus Therapeutics, Novartis, and Miltenyi Biotec are major players sponsoring ongoing development efforts, but a vast number of small biotech companies are also working in this space. Therefore, several mergers and acquisitions have taken place in the market. For instance, in October 2017, Gilead Science acquired Kite Pharma, a leader in engineered T-cell therapy, for $11.9 billion, and then in December 2017 acquired Cell Design Labs for $600 million to extend its cellular therapies platforms. Similarly, Celgene acquired Juno Therapeutics for $9 billion in 2018 and then Bristol-Myers Squibb (BMS) acquired Celgene for $74 billion in 2019. Also in that year, Astellas Pharma acquired Xyphos Biosciences and its CAR T-cell technology for $700 million.

The CAR T-cell therapy market is expected to continue witnessing the highest total revenue share from North America over the next five years. However, a major strategic focus from big pharmaceutical companies is toward Asia, as India is densely populated and reaches over 2 to 3 million new cancer cases per year. (According to the World Health Organization, 18.1 million cases and a death toll of over 9.6 million from cancer were reported in 2018 worldwide.) Likewise, China is emerging as a leader in the development of novel CAR T-cell therapies.

Scenario in Asia:

China has alone registered 357 clinical trials for CAR T-cell therapies, of which 175 trials are for CD19-directed products. In China, cancer immunotherapy using T cells has been practiced in the clinic for many years, including lymphokine-activated killer (LAK) therapy since 1988 and cytokine-induced killer (CIK) therapy since the late 1990s.

However, the benefits from these therapies were minimal, and the clinical benefit of CAR T-cell therapy inspired Chinese researchers to carry out domestic CAR T trials. In addition, in 2015, the Chinese government issued new policies for cellular therapy, stating that this type of therapy could be carried out only in clinical trials. Thereafter, CAR T-cell therapy replaced other existing therapies, and China replaced the United States as the country with the highest number of clinical trials in CAR T-cell therapy in 2017.

In June 2021, Fosun Kite Biotechnology, a joint venture of US-based Gilead and Chinese Fosun Pharma, received the first Chinese approval for a CAR T-cell therapy for FKC-876 (axicabtagene ciloleucel). This CD19-directed CAR T therapy is marketed as Yescarta (axicabtagene ciloleucel) in the United States and European Union. The second approved CAR T therapy in China was Carteyva (relmacabtagene autoleucel) in September 2021. This CD19 CAR T-cell therapy was manufactured by JW Therapeutics, a joint venture between US-based Juno Therapeutics (part of BMS) and Chinese WuXi AppTec. JW Therapeutics invested in a $300 million Hong Kong IPO and collaborated with Shanghai Pharma for national distribution and logistics.

International collaboration is also in progress to fuel the CAR T-cell market. For instance, in December 2017, US-based Janssen Biotech, the R&D unit of J&J, signed a worldwide collaboration and license agreement with Chinese Legend Biotech for CAR T-cell therapy (ciltacabtagene autoleucel) and has filed for FDA review in multiple myeloma.

Similarly, US-based Allogene Therapeutics and Chinese Overland Pharmaceuticals announced the formation of a joint venture in December 2020 to prepare Allogene’s allogeneic CAR T-cell therapy AlloCAR T for patients in Greater China, Taiwan, South Korea, and Singapore, with Overland gaining an exclusive license to develop, manufacture, and commercialize specific Allogene candidates in these areas. AlloCAR T will treat hematologic malignancies and solid tumors, with an estimated investment of $117 million.

Finally, an agreement between Chinese Shenzhen Pregene Biopharma and Indian Dr. Reddy’s Laboratories was announced in May 2021 to acquire the exclusive rights in India for Pregene Biopharma’s PRG1801, an anti-BCMA CAR T cell therapy injection. Pregene Biopharma is expected to receive payments in series of $5 million for the first indication, $7.5 million for subsequent indications, and $150 million on future sales.

Current concerns and side effects:

The growing industrial investment, potential clinical trial accomplishments, and regulatory approvals of CAR T-based drugs reflect the bright future of this technology. However, high treatment costs remain a real concern. For example, although hundreds of medical centers are certified to offer CAR T-cell therapy, Medicare does not cover the entire reimbursement. This is a major challenge for health systems seeking to manage the high cost of these products and services.

According to the American Society of Clinical Oncology, the median drug cost alone is $411,278, the median total cost of care for CAR T-cell therapy is $610,999, and the total cost of care could exceed $1 million, depending on the case. In addition, CAR T-cell therapy can cause serious or even life-threatening side effects, including cytokine release syndrome and nervous system problems, so it can only be given under expert supervision in medical centers.

The standard route of taking a patient’s T cells to generate CAR T cells (autologous therapy) brings its own set of logistical challenges. Therefore, researchers are also pursuing allogeneic CAR T-cell therapy; however, as the T cells are taken from healthy donors in this technology, this therapy can lead to serious rejection from the host immune system, including graft-versus-host disease, host-versus-graft-disease, and attack by a patient’s natural killer (NK) cells. However, scientists have now developed a gene-editing system to engineer the CAR T cell to overcome this barrier. This novel discovery can decrease treatment cost and time of overall therapy, and may even be used to develop universal CAR T cells for the treatment of multiple cancers.

Summary and conclusions:

Briefly, CAR T-cell therapy for cancer has demonstrated promising clinical response rates. Recent FDA drug approvals, an expanding CAR T market, and growing clinical trial registrations are a few factors that reflect the dominance of CAR T therapy in coming years. However, high treatment costs and the risk of severe side effects are yet to be overcome. Current advances and future research efforts must address these issues

To date, efforts involving CAR T-cell therapies have focused on serious conditions such as myeloma and related incurable diseases that have no acceptable alternative, but which are amenable to administration of CAR T regimes. Myriad approaches are now underway to extend the range of molecular targets and improve treatment efficacy in these conditions. A next major challenge will be in the treatment of solid tumors, where promising early results show that the combination of CARs with checkpoint blockade and the suppression of other inhibitor factors can overcome the challenge of the immunosuppressive tumor microenvironment in solid tumors.

Improvements upon the CAR design, including next-generation approaches targeting additional antigens and improving therapy efficacy, development of allogeneic CAR T-cell therapies, combination with other treatment regimes, and advances in delivery mechanisms are driving rapid progress to expand the applications of this technology toward the cure of other presently non-curable diseases. 

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