The excitement around cell therapy as a game-changing treatment option is hard to miss. The volume of ongoing trials across a range of modalities and targets and the billions in public and private funding for a growing number of companies in the space highlight an alignment between scientists, investors and entrepreneurs in thinking this may be the next frontier of medicine. While many developments are ongoing in approaches beyond chimeric antigen receptors (CAR), CAR-T maintains the top position and is the only cell therapy type to boast an FDA approval (5 as of Sep’21, with J&J & Legend’s cilta cel likely being the 6th by Nov’21). While there is a lot to cover in the space, this post is meant to serve as a crash course into CAR-T cell therapy: what it is, how it works and where it is headed.

What is CAR-T cell therapy?

Cell therapy is the treatment of disease by restoring or altering certain sets of cells or by using cells to carry a therapy through the body. Under that definition, cell therapy includes ‘typical’ treatments such as blood transfusions, but when used colloquially, it is often referring to gene-modified cell therapy, whereby cells are cultivated or modified ex-vivo (outside the body) before being injected into the patient.

The CAR T cell therapy process. T cells are isolated from blood of the patient or a donor, activated, and then genetically engineered to express the CAR construct (an example shown in gray above the vector particle in violet). After ex vivo expansion of the CAR T cells, they are formulated into the final product. The patient undergoes either a conditional chemotherapy or the CAR T cell product is directly infused.

Source: Hartmann, Jessica, et al. “Clinical Development of CAR T Cells-Challenges and Opportunities in Translating Innovative Treatment Concepts – Semantic Scholar.” Undefined, 1 Jan.1970, www. embopress.org/doi/full/10.15252/emmm.201607485

Immunotherapy is short-form for cancer treatment that leverages the immune system, which includes monoclonal antibodies, immune checkpoint inhibitors and cell therapy, among others. Cell therapy-focused immunotherapy approaches revolve around adoptive cell transfer (ACT), whereby an immune cell (oftentimes a T-cell) is reprogrammed in the lab and injected into a patient in order to better identify and kill cancer cells. A CAR is an example of an ACT – a vehicle through which reprogrammed immune cells can be directed against cancer cells. While a CAR can be used for different immune cells (i.e. CAR-NK or CAR-M), it is most often paired with T-cells, thus the term CAR-T.

How does CAR-T cell therapy work?

Mechanistically, CARs are engineered receptor proteins that direct T-cells against a specific antigen present on the surface of cancer cells. It does this by combining antigen-binding properties [via an extracellular single-chain variable fragment (scFv)] with T-cell activating functions. In this way, CAR-T cells create a link between extracellular ligand recognition domains and intracellular signaling molecules, which ultimately activates T-cells against the antigen of choice.

Schematic representation of a T cell receptor (TCR) and four types of chimeric antigen receptors (CARs) being displayed on the surface of a T cell while contacting their antigen (red) on the tumor cell. The single-chain variable fragment (scFv) as ligand-binding domain mediating tumor cell recognition in CARs is shown in light blue with the VH and VL domains being connected via a long flexible linker and transmembrane domain to intracellular signaling domains. Pro-inflammatory cytokines or co-stimulatory ligands expressed by the CAR T cells are depicted for the 4th generation.

Source: Hartmann, Jessica, et al. “Clinical Development of CAR T Cells-Challenges and Opportunities in Translating Innovative Treatment Concepts – Semantic Scholar.” Undefined, 1 Jan.1970, www. embopress.org/doi/full/10.15252/emmm.201607485

CARs were first designed in the late 1980s and have undergone various improvements over the years thanks to their modular design. In general, there are 4 distinct ‘generations’ of CAR design, with many additional improvements currently being tested.

2nd generation CARs are the basis for currently approved CAR-T cell therapies.

Source: Subklewe, M., von Bergwelt-Baildon, M., & Humpe, A. (2019). Chimeric Antigen Receptor T Cells: A Race to Revolutionize Cancer Therapy. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie, 46(1), 15–24. https://doi.org/10.1159/000496870

When it comes to the source of the starting cell material, there are two flavors: the cells can come from the patient themselves (known as autologous cell therapy) or from healthy donors (known as allogeneic cell therapy). Autologous cell therapy is the ‘original’ CAR-T cell therapy, and all FDA-approved products are of this type. Allogeneic methods are an exciting development that could simplify the manufacturing process and allow for ‘off-the-shelf’ therapies manufactured well in advance of a patient’s need. Below we compare the relative pros and cons of each approach in more detail.

Different approaches: autologous vs. allogeneic CAR-T cell therapy

While avoiding the immunological mismatch of Allo-CAR-T remains an ongoing problem, it is clear that should Allo-CAR-T achieve the durability of Auto-CAR-T, it would become the clear choice for most physicians and payors, with the exception of bespoke usage with certain patients.

Much of this comes down to manufacturing, dosing and cost – allogeneic cell therapies are immediately available for patients, which is critical as most current patients have relapsed on other therapies and are using CAR-T as a last resort. They do not have the luxury of time and even a multi-week delay in treatment could be fatal. Additionally, Allo-CAR-T promises to be far cheaper and safer to manufacture due to economies of scale:

• A single manufacturing run can produce multiple doses
• The higher quality starting cell material should offer a more consistent and potent final product
• Reduced time pressure will result in increased use of automation, higher-quality storage and transportation and more robust quality control
• Reduced reliance on expert stem cell scientists who may be prone to operator bias and scaling difficulties

All of this should provide ample cost efficiencies that drive down the price of CAR-T and make it a more accessible treatment option to patients regardless of prior treatment (i.e. lower cost justifies shift into 2L or earlier) or geography. Currently, only a select number of cancer centers across the country are equipped to dose CAR-T and they tend to concentrate around major metropolitan areas, resulting in many patient’s families racking up large travel and lodging costs just to receive care. Regional ‘cell banks’ housing Allo-CAR-T doses would reduce the need to travel to established care centers.

Auto-CAR-T is also limited by the highly variable health of the patient’s T-cells, which can be impacted by age, cancer type, duration of disease and prior therapies. Since these patient populations are heavily pretreated, it is common for autologous products to fail to expand or transduce well. Healthy donors will have far more naive T-cells and memory T-cells than cancer patients, which generally translates to higher persistence and increased long-term therapeutic impact. Patients may also be able to be re-dosed with Allo-CAR-T due to the cell source being healthy donors (greater number of CAR-T cells and batches produced) vs. the sick patients’ themselves with Auto-CAR-T. However, repeated dosing would require careful management of immunological rejection or complications associated with repeated immunosuppression.

The biggest hurdle for allogeneic cell therapies remains the relatively poor persistence vs. autologous therapies. This was demonstrated most recently with CRISPR’s 6-month complete response rate of 21% for their 24 patient LBCL cohort (vs. Wall Street estimates of ~30%). While much could be said about whether CRISPR is pursuing cell therapy as a ‘me too’ project, the fact remains that achieving durability in line with Auto-CAR-T therapies will be critical to achieving mainstream physician and patient acceptance. The allogeneic manufacturing advantage comes into play once drugs are on-market, but efficacy and durability are key to getting there to begin with.

With both approaches, the most significant risk with CAR-T remains cytokine release syndrome (CRS), a systemic inflammatory response common after administration of T-cell engaging therapies. CRS can range from mild, flu-like symptoms to severe, life-threatening multi-organ system failure. The current treatment algorithm for CRS varies based on severity and is constantly evolving given the relatively recent introduction of CAR-T therapies, but usually involves a combination of antihistamines, antipyretics, antibiotics, corticosteroids and fluids. The complexity of treatment revolves around managing symptoms while avoiding mitigation of the anti-tumor immune response.

Manufacturing and supply chain considerations

It is helpful to remember that cell therapies are living drugs and thus the complexity around manufacturing, transportation, testing and dosing is amplified. With current autologous CAR-T therapies, batches are typically small and bespoke to each patient, preventing significant automation or economies of scale. The unique situation of each patient means that the starting material collected is highly variable and may require manual manipulation at various stages throughout the manufacturing process. All of this amounts to a system with both open and closed components, limited automation, high risk of contamination, variable product consistency and high costs.

Even with marketed products such as Kymriah and Yescarta that have been approved for a few years, it is clear that clinical development far outpaced manufacturing scale-up, resulting in outdated analytics, quality control concerns and an insufficient supply chain. In order for cell therapies to become ‘mainstream’, front-line therapies for most patients, an industrialized manufacturing system must be implemented that results in a faster, safer and cheaper final product.

Autologous CAR-T manufacturing vs. Allogeneic CAR-T manufacturing

Looking ahead, a more decentralized manufacturing process will be essential to make cell therapy a more mainstream treatment option. Currently, most products have to be shipped back and forth, given the limited number of centers that can produce CAR-T therapies. However, shipping cells and vectors from coast to coast or around the world invites both logistical and regulatory challenges, particularly during the COVID era where there may be heightened restrictions.

All of this points to a more locally sourced manufacturing process. One of the ways this is currently being done is Miltenyi’s CliniMACS Prodigy machines, an all-in-one device that supports cell processing, cell separation and formulation of the final product. Since Prodigy is a closed system, it reduces cleanroom requirements, contamination risk and human error. Since it is automated, it produces a standardized, GMP-compliant cell product over and over again. The Prodigy can also be easily implemented into academic centers across the country, reducing the centralized concentration of cell therapy centers and the need to ship cells long distances. While the final product may not be 100% identical between different locations, it is a huge step forward towards a streamlined, decentralized manufacturing process.

The CliniMACS Prodigy device.

Source: Miltenyi Biotec

Further down the road are approaches such as Cellino Biotech’s AI-guided laser editing platform, which may allow for the potential scaling of Auto-CAR-T. It is worth mentioning to showcase that manufacturing innovation is occurring across the cell therapy space, for both current and next-generation products.

Current competitive landscape and beyond

As of Sep’21, 5 Auto-CAR-T products are approved by the FDA for the treatment of hematological malignancies. While the true competitive landscape would encompass therapies across all modalities, we will focus on the substantial pipeline and developments within CAR-T specifically. For a view on the broader cell therapy landscape, consider checking out our 2021 Cell Therapy Landscape post.

Overview of currently approved CAR-T therapies. The B-cell specific antigen CD19 has been the most common target.

Source: company filings.

Currently, these therapies are restricted to the 3L+ setting after patients have relapsed on other therapies in the treatment paradigm. However, Gilead, Novartis and BMS are all currently running trials designed to justify a label expansion into 2L or earlier treatment lines. As long-term data accumulates and manufacturing challenges are addressed, KOLs have expressed interest in utilizing CAR-T as a front-line treatment option due to the curative nature of the therapy. Additionally, since the health of patients’ T-cells is negatively impacted with each round of chemotherapy, there is a desire to ‘maintain’ T-cell fitness and move directly to CAR-T therapy earlier.

Beyond these FDA-approved products is a rich pipeline of Auto-CAR-T and Allo-CAR-T assets at various stages of preclinical and clinical development. Below we have highlighted a few key players, but encourage anyone interested in understanding the complete competitive landscape to consider checking out our 2021 Cell Therapy Landscape post.

Bold represents FDA approved assets, with J&J / Legend’s cilta-cel assumed to be approved November 2021

While the majority of currently approved products target the CD19 antigen for B-cell malignancies, next-gen therapies in the pipeline are targeting a diverse range of antigens across various tumor types.

Next-gen CAR-T therapies are targeting a broad range of tumor antigens.

Next-gen pipeline assets are also exploring a number of approaches designed to enhance efficacy and safety, with select approaches highlighted below.

Source: Weber EW, Maus MV, Mackall CL. The Emerging Landscape of Immune Cell Therapies. Cell. 2020 Apr 2;181(1):46-62. doi: 10.1016/j.cell.2020.03.001. PMID: 32243795.

It should be noted that there is a significant lag time between FDA approval and when the underlying technology was discovered. As noted earlier, currently marketed CAR-T therapies are based on 2nd generation CAR constructs and technologies discovered 5-10+ years ago. As a result, the safety (i.e. high risk of CRS) and efficacy (i.e. ineffective in solid tumors) limitations of currently approved CAR-T therapies are likely to be addressed with the next generation of approved products and combinations.

For more detail on the current CAR-T competitive landscape alongside a number of other innovative modalities, including TCR-T, CAR-NK, TILs, Gamma Delta T-cells, CAR-M, APCs and more, consider viewing the 2021 Cell Therapy Landscape post here.