One of the most promising and rapidly evolving fields in modern medicine, CAR T-cell therapy is a relatively new cancer treatment with the potential to transform management of one of our most prevalent and deadly diseases. Where the conventional treatments of today are well known for the often devastating collateral damage caused, CAR T-cell therapy can target and eradicate cancer cells with fewer effects on surrounding healthy tissues. With proper democratization, CAR T-cell therapy stands to make chemotherapy and other taxing, intensive treatment methods part of healthcare's past.
But how does CAR T-cell manage to outperform other treatments in this way? By what mechanism does it succeed where so many other methods have underperformed? The answers to these questions are crucial to understanding how and why this treatment must be democratized, and they lie within the mechanisms at work in every human body at a cellular level.
Part of the body's natural immune response, T-cells are white blood cells belonging to the lymphocyte category. Geared towards providing precise and durable protection against the various bacteria, viruses, and microbes encountered by the human body each day, these cells utilize receptors on the outer surface of their membranes to detect specific antigens, typically protein-based, residing on the surface of invading cells. Once detected, the T-cell receptors (TCR) recognize these antigens as a threat and begin to generate signals within the T-cell instructing it to eliminate this threat.
The CAR T-cell is distinct in that it is man-made. Rather than naturally generated TCRs, the CAR T-cell utilizes Chimeric Antigen Receptors (CARs), which function exactly like native receptors but are specifically programmed to target cancer cells of interest. Upon detection, CARs attach to the offending cell and begin the elimination process like TCRs do with common threats encountered daily.
Unsurprisingly, it requires a complex genetic process to generate these custom receptors and train the T-cell in this way. In this process, researchers must instruct the T-cell to express CAR receptors on its membrane by introducing it to foreign DNA or RNA. Yet, this process results in a "living drug," one that not only intelligently combats the disease in question but continues doing so well past when treatment is administered.
From a treatment perspective, we may look to the high-level workflow of autologous T-cell therapy, one of the method's most common iterations, to get an idea of what this process looks like. It is as follows:
This illustrates the fundamental process by which T-cell therapies are generated. Within subsequent blogs we will provide a deeper dive into this production process.
Although the fundamental process of CAR T-cell is the same across therapies, they differ according to format. Format, in this case, depends on where the CAR T-cells are generated, meaning there are two main formats for these types of therapy: Ex-Vivo or In-Vivo.
While all formats of CAR T-cell therapy can target cancerous cells while leaving healthy tissues untouched, there are notable differences in the benefits provided by the Ex-Vivo autologous and allogeneic formats, respectively.
In the case of autologous formats, because the therapy is a one-to-one solution derived from the patient and custom-made for them, providers need not worry about biological mismatches.
On the other hand, allogeneic formats offer several benefits, making them well-suited for vast dissemination. This format is scalable, being able to treat approximately 100 patients from a single manufacturing run using one donor biomaterial. Unlike autologous therapies, allogeneic treatments are considered "off-the-shelf," available for immediate use at point-of-care by the patient without time-consuming production processes. Subsequent blogs in this series will outline how to achieve “allogeneic benefits” at point-of-care with an efficient, standardized autologous production process.
Common advantages for both autologous and allogeneic CAR T-cell therapy is that they continue to be effective for months following treatment, as the cells continue to live in the body, fighting cancer and preventing relapse. Additionally, the therapy session is often one-time, providing benefits to the patient’s lifestyle because it’s a living drug.
Of course, any medical treatment contains the possibility of complications and side effects, and CAR T-cell therapy is no different.
The disadvantages inherent in ALL types of CAR T-cell therapy include:
Standard supportive therapies, such as steroids, are sufficient to manage mild forms of this syndrome.
In the case of Ex-Vivo CAR T-cell therapy, there are distinct disadvantages depending on whether the treatment is autologous or allogeneic, with the former seeing challenges in production while the latter more often encounters issues relating to the compatibility of donor cells with host cells.
The most significant disadvantage of autologous therapies is, without a doubt, the "vein-to-vein" turnaround time required to produce custom treatments. Autologous T-cell therapies are produced per patient, a process that can take several weeks in itself. They must also be developed at a centralized lab location, requiring freezing/ thaw cycles and transportation causing delays. Additionally, autologous therapies are bespoke, suffering from a high degree of exclusivity because of this need for a centralized lab, as limited production slots are available at any given time. Unfortunately, many patients cannot afford to wait out the development period, let alone procure a place in production. Subsequent blogs in this series will outline a point-of-care production methodology to relieve this issue.
Allogeneic therapies trade the disadvantages of bespoke production for the challenges of dealing with donor and host materials. Although they may be more readily accessible and easily scaled, allogeneic treatments can run into many issues if there is an inherent immunological difference between the donor cells used in production and the patient's immune cells. These include:
One prevention strategy is deploying immunosuppressive treatment regimens to induce lymphodepletion before administering allogeneic T-cell therapy. Yet, this increases the risk of contracting opportunistic infections.
While the In-Vivo format is still a nascent approach, it promises to capture the efficacy of autologous cell therapy while lacking any of its connected logistical challenges. It also promises to be as scalable and easy to produce as any allogeneic therapy. It does, however, have its own unique set of challenges.
Where immunosuppressants can reduce complications in the case of other T-cell therapy types, lymphodepletion cannot be performed in the case of In-vivo treatments. This is because any immune system depletion would eliminate the very cells targeted by the In-vivo therapy.
Further, In-vivo therapies must be very carefully developed, with a vehicle for delivering genetic material that is highly selective, to ensure that only T-cells are being targeted. Otherwise, the treatment may cause off-target cells to undergo unwanted gene modifications, a complication that can have an untold negative impact.
In our next blog installment, we'll look at how CAR T-cell performs against different types of cancer, including hematological malignancies and solid tumors. Visit the MIDI Innovation Vault to learn more.