Cell therapy has undergone a transformative evolution, reshaping cancer treatment paradigms through groundbreaking innovations like chimeric antigen receptor (CAR)-T cell therapies. These therapies have seen significant advancements in recent years, reflecting a broader trend towards personalized and targeted treatment options. With six FDA-approved CAR-T therapies on the market targeting hematological cancers such as B-cell lymphomas and multiple myeloma, CARs are likely to experience more and more interest from researchers looking to expand their therapeutic potential and optimize their efficacy and safety profile.
To date, FDA approvals for CAR-T therapies have been confined to hematological malignancies. Expanding their efficacy to other cancer lineages, particularly solid tumors, remains challenging, with only limited success achieved so far. As such, significant efforts are being made to enhance the efficacy of CAR-T therapies, as well as to broaden their therapeutic application window. These include research into generating multi-specific CARs able to hold affinity for more than two different types of antigens as well as into reducing side effects, so these therapies can be administered without the need for complementary treatments. Furthermore, cell therapy technologies are advancing beyond T cells to encompass other cell types such as natural killer (NK) cells, macrophages, and emerging modalities like tumor-infiltrating lymphocytes (TILs), dendritic cells, cytokine-induced killer (CIK) cells, and in vivo CAR-T strategies. Each of these offers unique advantages for a more diverse array of oncological applications. For example, CAR-Ms (macrophages) are able to infiltrate solid cancer cells more effectively, making these cells more suitable than CAR T-cells for these oncological indications.
As the landscape of CAR T-cell therapies evolves, these treatments are becoming more precise in targeting cancer cells and overcoming production challenges, poised to revolutionize oncology. To fully realize this potential, a two-pronged approach is essential: rigorous in-depth characterization to comprehensively assess safety and efficacy, coupled with the exploration of CARs endowed with novel properties to expand the treatable range of cancers.
The Future of CARs: Solid Tumors, Autoimmune Disorders, and Beyond
Natural killer (NK) cells, lymphocytes that both demonstrate direct effector functions against specific cellular targets and generate and maintain multicellular immune responses, have seen increasing research interest, particularly in combination with CAR technologies for oncological indications. CAR-NKs possess a similar mechanism of action to CAR-T therapy, where tumor cells are killed through cytotoxicity. CAR-NKs, however, possess a few key advantages over CAR-T therapies related to their production and the body’s own response to these therapies. One of the main disadvantages of CAR-Ts are their potential to induce cytokine release syndrome (CRS), which can lead to severe, possibly fatal, side effects. Because NK cells induce the production of a different spectrum of cytokines, they do not have the same potential to trigger CRS. CAR-NKs can also be manufactured from multiple sources not originating from the patient, allowing a more scalable method of allogeneic production that can be used in a wide range of patients.
CAR-NKTs (natural killer T cells) are another emerging modality that has the potential to overcome the limitations of both CAR-T and CAR-NK applications. These CAR-NKTs, which possess natural anti-tumor properties and narrow localization to tumor sites, have demonstrated no significant side effects for normal cells.1 CAR-NKTs are also able to regulate the immune system and exist in both blood and tissue, making CAR-NKT therapies potentially more effective in solid tumors. CAR-NKT therapies are also able to be manufactured without using the patient’s own cells, allowing “off-the-shelf” production and minimizing time and costs for these treatments.
When it comes to CARs that can more effectively target solid tumors, CAR-M applications likewise offer distinct advantages over CAR-Ts. Because CAR-M therapeutics are able to more effectively infiltrate and interact with the tumor microenvironment to induce an immune response, they can interact and kill the tumor cells in synergy with recruited immune cells. Moreover, because it is challenging to cultivate iPSCs in a manner that effectively maintains the M1 phenotype, CAR-Ms are often leveraged to better facilitate their production.
Another recently approved form of therapy, Tumor-Infiltrating Lymphocyte (TIL) cell therapy is a groundbreaking treatment for certain types of cancer, and has shown promising results in clinical trials, particularly in patients with advanced melanoma, cervical cancer, and certain types of lymphoma. TIL therapy involves extracting immune cells called T cells from a patient's tumor, growing them in large numbers in a lab, and then infusing them back into the patient. These T cells, which have been trained to recognize and attack cancer cells, can then mount a more effective immune response against the tumor.
One of the key advantages of TIL therapy is its ability to target a wide range of cancer types, as the treatment is customized to each individual patient based on their specific tumor characteristics. Additionally, TIL therapy has demonstrated durable responses in some patients, with the potential for long-term remission. However, like any medical treatment, TIL therapy also comes with potential risks and side effects, including immune-related adverse events and the need for careful monitoring and management of these complications.
Finally, cytokine-induced killer (CIK) cells represent a potent subset of immune cells with regulatory and cytotoxic capabilities, classified within the T cell category. These cells, which can occur naturally or be cultivated in the lab, play a crucial role in enhancing immune responses and targeting tumor cells for destruction. CIK cells are produced by stimulating extracted T cells with specific cytokines, such as Interleukin-2 (IL-2). This significantly boosts their ability to identify and eliminate tumor cells, leveraging their natural propensity to recognize tumor-associated antigens that are overexpressed on malignant cells and making them particularly effective against metastatic cancers. As research progresses, CIK cell therapies continue to demonstrate their value by offering more effective treatment options for patients with advanced and difficult-to-treat cancers. This ongoing development not only broadens the scope of immune cell therapy but also promises to deliver more personalized and potent cancer care solutions.
The Pros and Cons of CAR Development Today
In oncology, traditional forms of treatment, such as chemotherapy and radiation therapy, are proven to be effective in killing cancer cells. But this efficacy comes at a cost ― chemo and radiation alike are non-specific, killing other healthy surrounding cells and resulting in a wide range of undesirable side effects. In contrast, CAR-based therapies target only tumor-associated antigens that are abundant in or specific to their targets, so that, ideally, healthy cells are mostly left intact, resulting in less severe side effects. As these therapies are also tailored toward a patient’s needs and directed at specific cells, they can result in higher efficacy when compared to traditional treatments. Since these cells are also patient- or donor-derived and are living, CAR-based therapies can persist inside the body for significant periods of time, conferring protection even after remission ― and potentially, in the event of recurrence.
While CAR-based therapies can be effective in certain situations, these applications still face one very significant hurdle during development: because CARs rely on the specific binding of a single antigen found on the surface of tumor cells, the treatment is ineffective if this binding does not occur. Also known as antigen escape, this major limitation causes the cancer cell to become resistant to treatment, resulting in a partial or complete loss of antigen expression, making binding difficult or impossible in certain cases.
There are additional challenges to overcome in pursuing CAR applications for solid tumors. Because they are surrounded by the physical barrier of the tumor microenvironment, including immunosuppressive cells that can inhibit the function of CAR cells, solid tumor cells undergo very little exposure to these treatments, resulting in low efficacy. Additionally, solid tumors express a wide variety of antigens that are often exclusive to small batches of cells, making them difficult to target with the same binding capabilities of the CAR treatment.
The Means of Production: Autologous vs. Allogeneic, In Vivo vs. Ex Vivio
The possibility of allogeneic production for CAR applications represents a significant leap forward for the space. Current approved CAR-T therapies are produced autologously, which has the advantage of being highly effective in patient treatment as well as eliminating the potential for graft-versus-host disease. There are a number of limitations to this autologous production paradigm; however, because these treatments are unique to an individual patient, their manufacture is also highly bespoke, requiring significant time and capital to produce individual doses. While other forms of treatment can be applied immediately, autologous production takes considerable time to fully develop, which can be challenging for often very sick patients that have already undergone multiple other lines of treatment. As each product is also typically decentralized in its production, autologous CARs must go through a longer QA/QC testing phase than other conventional therapies, leading to an even greater delay.
Allogeneic manufacturing can serve to address many of these limitations, enabling a paradigm where the mass manufacture of CAR treatment can be accomplished through leveraging healthy donor cells to generate drug substances at greater scales. This can allow for treatments that are dispensed “off-the-shelf” immediately, lowering the wait time for patients considerably and vastly improving the economies of scale, in turn lowering the price of treatment for patients. However, allogeneic production also faces a major limitation to its widespread development: as the cells are not of host origin, they have the possibility of exhibiting major histocompatibility complex (MHC) incompatibility, as well as having different T cell receptors (TCR), which can likewise cause graft-versus-host.
Currently, all FDA approved CAR applications are produced through ex vivo approaches wherein cells are genetically modified outside of the body and then re-introduced later. In contrast, in vivo applications, which consist of an “off-the-shelf” product that can be mass produced and injected into most patients, have the potential to combine both the advantages of autologous and allogeneic production. These therapeutics enter the host and transduce the host’s cells to become genetically modified, effectively resulting in autologous CAR cells. This would allow time and cost of production to be lowered significantly while continuing to provide the benefits of autologous production and to avoid any side effects that may occur with allogeneic production.
However, there are still multiple limitations before in vivo applications can be readily pursued. There are a variety of vectors that can be used to transduce the host’s cells. In this regard, genotoxicity from misplaced insertions by the vector must be considered, as these insertions could possibly lead to the creation of an oncogene, resulting in cancer in the patient. As CAR-T therapy often leads to CRS side effects, a permanently transduced CAR cell may lead to the same side effects in the host. Methods for controlling the activity of the transduced CAR cells must therefore be established to avoid these side effects. The host’s immune system may also react negatively to the vectors and rapidly remove them from the system before they can transduce the cells, leading to lower efficacy as CAR cells are not generated in the host.
Paving The Way For CARs
To make CAR T-cell therapies safer and more effective, scientists need to better understand how they work inside the body. This requires strong analytical tools to track several things, including:
Cytokine release: These signaling molecules can cause significant patient side effects and immunogenicity. As such, measuring them effectively helps ensure patient safety. T cell activity: Measuring T cell proliferation and persistence can serve to help understand cytokine release, as well as the ultimate efficacy of a CAR therapy. CAR persistence in tumors: Assessing how well the therapy is working against solid tumors will be key to expanding their applications for other cancers in the coming years. Tumor escape mechanisms: By understanding how tumors avoid CAR T-cells, scientists can develop improved therapies in the future.
Understanding the structure of a CAR therapy is likewise necessary to increase its efficacy in the body. There are constant improvements and new generations of CAR therapy being developed, and with these changes in structure come changes to their efficacy in binding, in turn increasing cell recognition and killing. A robust analytical strategy is required for the molecular profiling of tumor cells; in particular, biomarkers exclusive to a tumor cell should be analyzed in order to tailor treatments that prevent healthy cells from being the target of a therapy. By analyzing multiple tumors, a common pattern may be discovered that could lead to the development of CARs that can target multiple different types of tumors. Additionally, a focus on analytics is crucial for emerging modalities such as CIK and TIL therapies in order to enable their broader applicability in the space. By leveraging these analytics to predictively identify possible responses and gains in efficacy, organizations can pave the way for CARs that are less immunogenic, more efficacious, and primed to treat some of the most intractable cancers.
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