CAR-T Cell Therapy: Beyond Hematological Cancer
- caitlinraymondmdphd
- Jan 6
- 6 min read
Updated: Feb 8
Introduction
CAR-T cell therapy has revolutionized the treatment of hematological cancers by harnessing the power of the immune system to specifically target and destroy malignant cells. This innovative approach involves modifying T-cells to express chimeric antigen receptors (CARs), which enable precise antigen recognition and potent immune activation. While initially developed to combat hematologic malignancies like leukemia and lymphoma, the therapeutic potential of CAR-T cells has expanded significantly. Researchers are now exploring its application in diverse areas, including autoimmune diseases and solid tumors, paving the way for novel treatment paradigms.
In this article, we delve into the foundational mechanisms of CAR-T therapy and its evolving applications. From the sources of T-cells to cutting-edge genetic engineering techniques, we explore how advances in technology are optimizing the efficacy and safety of CAR-T cells. The article also examines how this approach is transforming the management of autoimmune disorders by offering a targeted, immune-resetting solution. Finally, we discuss the unique challenges posed by solid tumors and the innovative strategies being developed to overcome them. Together, these insights highlight the vast potential of CAR-T therapy to address some of the most challenging conditions in medicine today.
Genetic Modification of T-Cells
CAR-T cell therapy involves genetically modifying T-cells to recognize and destroy specific targets. Modified T-cells express a CAR which combines the extracellular domain of an antibody with the intracellular domain of a T-cell receptor along with a co-stimulatory molecule. Thus, the finely tunable antigen recognition of an antibody is coupled to T-cell activation, which results in destruction of the target. The expression of CAR constructs involves introduction of a larger amount of genetic code, and for this purpose lentiviral vectors are often used because they carry a large payload (~10kb). The benefits of lentiviral vectors include integration into the genome and stable expression of the CAR construct. Moreover, lentiviral vectors can integrate into many cell types, including non-dividing cells. However, integration into the genome will be random and may result in insertional oncogenesis, whereby the vector itself increases cancer risk. Typically, manufactured T-cells are screened for lentiviral copy number at the end of manufacturing, with a copy number ≥ 5/cell indicating increased risk for oncogenesis.
Recent studies are pioneering the use of CRISPR editing in CAR-T cells to reduce therapy risks and enhance performance. CRISPR gene editing involves creating a double-stranded break at a specific sequence, which can then be used to either disrupt expression of a gene (“knock-out”) or edit the gene itself. In CAR-T cell therapies, CRISPR is being used to knock out the cell’s endogenous T-cell receptor to reduce risk of GvHD, the cell’s expression of MHC molecules to reduce risk of graft rejection and failure, and inhibitory regulators of T-cells to enhance function. There is also ongoing research into using the CRISPR system to insert the CAR construct itself into specific places in the genome, which avoids the inherent insertional oncogenesis risk of lentiviral vectors.
Sources of T-Cells
Currently, the gold standard for CAR-T cell therapy is collection of cells outside the body, followed by genetic manipulation in a lab, and finally infusion of the modified cells back into the patient. For this process, different sources of T-cells are used, with each approach offering distinct advantages and challenges.
Autologous CAR-T Cells: Derived from the patient’s own T-cells, these therapies pose a lower risk of graft-versus-host disease (GvHD) and graft failure from immune rejection. These therapies also have a higher chance of long-term persistence, allowing for potential surveillance and destruction should the target return. Their longer lifespan makes them an ideal source for cancer treatments. Manufacturing challenges can arise due to the compromised quality of T-cells in patients with advanced diseases, and the bespoke nature of individualized therapies. However, as the longest utilized source of T-cells for CAR-T cell therapy, autologous cells have the most validated manufacturing protocols.
Allogeneic CAR-T Cells: Derived from healthy donors, these cells are hardier and easier to genetically modify. Moreover, one collection from one donor can be used to treat multiple patients. In this way, allogeneic CAR-T cells act as an ‘off-the-shelf’ cellular therapy. Despite these advantages, they carry a higher risk of graft failure via immune rejection and GvHD. They are also less likely to persist in the body over time, and may require multiple doses to achieve a therapeutic effect. Finally, as a newer technology, allogeneic CAR-T cells have less history behind them and need further study and validation.
In-Vivo CAR-T Cells: Finally, the newest ‘source’ of CAR-T cells doesn’t involve collecting cells outside a body at all. Cutting edge clinical trials are underway to test the idea that CAR-T cells can be ‘manufactured’ inside the body. This approach hinges on the use of gene vector that specifically targets a subset of cells. A large portion of ‘in-vivo’ CAR-T cell trials are using vectors based on the lentivirus backbone, which has been engineered to express an antibody-based cell targeting moiety, as well as various glycoproteins from other viral families to enhance uptake into the desired cell subset. However, other gene vectors - such as lipid nanoparticles - are being tested, with the most effective strategy yet to be determined.
CAR-T Therapy in Autoimmune Disorders
CAR-T cell therapies are rapidly gaining attention as a groundbreaking approach to treating autoimmune diseases by directly addressing the immune system abnormalities driving these conditions. Traditionally developed for cancer, CAR-T cells have been repurposed to target autoreactive B-cells, which produce the pathogenic antibodies responsible for many autoimmune diseases. These therapies use engineered T-cells to target CD19, a surface marker expressed on B-cells, leading to the selective depletion of both active and precursor B-cells in the patient’s body. This process induces a state of temporary B-cell aplasia, effectively eliminating the production of autoimmune antibodies. While all antibody production will be eliminated during the period of B-cell aplasia, benign antibodies can be replaced with IgG supplementation, and other arms of the immune system remain intact. Unlike traditional immunosuppressive therapies, which broadly dampen immune responses and dramatically increase infection risks, CAR-T cells provide a targeted and efficient solution, minimizing collateral damage to the immune system.
One of the most transformative aspects of CAR-T cell therapy in autoimmune diseases is its potential to act as an “immune reset button.” After several months of induced B-cell aplasia, the patient’s own B-cells regenerate, but without the autoreactive characteristics that fueled the autoimmune response. This not only resolves the immediate symptoms but also fosters long-term remission of disease. Early clinical trials have reported remarkable outcomes, with significant improvements in disease-specific symptoms, tissue repair, and overall immune system normalization. Notably, these benefits have been achieved with a favorable safety profile, as patients experienced no severe toxicity or relapse during follow-up periods. As research advances, CAR-T therapies could revolutionize treatment paradigms for refractory autoimmune diseases, offering a precision medicine approach with durable and potentially curative outcomes for conditions that were once considered untreatable.
CAR-T Therapy in Solid Tumors
While CAR-T cell therapy has shown remarkable success in hematologic malignancies, or "liquid tumors," translating this success to solid tumors has been more challenging due to the distinct characteristics of these cancers. One of the primary obstacles is the immunosuppressive tumor microenvironment (TME), which actively inhibits T-cell function. Additionally, solid tumors often exhibit antigen heterogeneity, meaning that tumor cells may express different or varying levels of target antigens, leading to potential evasion of CAR-T cell detection. Moreover, the antigens expressed by solid tumors are often not unique to malignant cells, leading to CAR-T cell recognition and destruction of benign cells and off-target toxicity. Finally, physical barriers such as dense extracellular matrix and irregular tumor vasculature further limit the infiltration and effectiveness of CAR-T cells. These factors necessitate innovative engineering strategies to enhance the potency and applicability of CAR-T therapies in solid tumors.
Several advancements aim to overcome these challenges and improve CAR-T therapy outcomes in solid tumors. Engineering CAR-T cells to secrete cytokines or chemokines helps recruit additional immune cells to the tumor site and counteract the immunosuppressive effects of the TME. Dual-targeting CARs, which recognize multiple antigens, address the issue of tumor heterogeneity by reducing the likelihood of antigen escape and helping contain CAR-T cell activity to only malignant cells. In a similar vein, including expression of novel co-stimulatory domains in CAR-T cells can enhance their activity, especially in the hostile tumor microenvironment. Furthermore, modifications to express enzymes like heparanase facilitate the degradation of the extracellular matrix, improving CAR-T cell penetration into dense tumor tissue. Safety enhancements, including switchable CAR designs and transient gene modifications, provide greater control over T-cell activity, reducing the risk of off-target effects and toxicity. Collectively, these innovations aim to enhance the persistence, efficacy, and safety of CAR-T cells, offering new hope for treating the complex and diverse landscape of solid tumors.
Further Reading:
1. Schett, G., Mackensen, A., & Mougiakakos, D. (2023). CAR T-cell therapy in autoimmune diseases. The Lancet, 402(10416), 2034-2044.
2. Schett, G., Müller, F., Taubmann, J., Mackensen, A., Wang, W., Furie, R. A., ... & Mougiakakos, D. (2024). Advancements and challenges in CAR T cell therapy in autoimmune diseases. Nature Reviews Rheumatology, 20(9), 531-544.
3. Albelda, S. M. (2024). CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nature Reviews Clinical Oncology, 21(1), 47-66.
4. Newick, K., O'Brien, S., Moon, E., & Albelda, S. M. (2017). CAR T cell therapy for solid tumors. Annual review of medicine, 68(1), 139-152.
