Analyzing the use of CAR-T Cell Therapy for Blood Cancers and Solid Tumour Cancer Types
Dhwani Patel, Ching Yung Yuan, Mackenzie Smith
December 2023
In recent years, immunotherapy has become increasingly popular as an option for cancer treatment. Immunotherapy harnesses the power of the patient’s immune system by directing immune cells to attack and eliminate cancer cells. There are many types of cancer immunotherapy, however, one particular type that has been significantly successful is CAR T cell therapy.
CAR T cell therapy manipulates a patient’s immune cells, T cells, to recognize and destroy cancer cells. Under normal conditions, T cells recognize foreign protein substances called antigens, which alert the immune system that there is something not right in our body, usually a bacterial or viral infection. CAR T cell therapy takes advantage of this immune response. To do this, special chimeric antigen receptors (CARs) are made in a lab specifically designed to recognize cancer cell antigens (1). The patient’s T cells are extracted and modified to express the CAR and are infused back into the patient, where the T cells can go on to form an immune response, and hopefully kill the cancer cells (1). The modification of a patient’s immune cells to attack a specific cancer allows for a personalized and more precise approach to therapy.
CAR T cell therapy has proven to be successful in non-tumor cancer types, specifically blood cancers. Blood cells make easy targets for CAR T cells since blood cells exhibit unique antigens that distinguish them from the rest of the body (2). This means that CAR T cells designed to target blood cell antigens are unlikely to interact with non-blood cells. Additionally, a lot of blood cancers have circulating cancer cells scattered throughout the body. Radiation, which works very well for localized tumours, cannot treat these scattered cancer cells. CAR T cells can be used in this case as they can seek out and kill blood cancer cells all over the body while sparing the other cell types that do not have the unique antigen (2). Due to its success in treating blood cancers, CAR-T cell therapy has been incorporated as an advanced treatment option for some aggressive blood cancers like acute lymphoblastic lymphoma and large B cell lymphoma (3). In patients who have initially received chemotherapy, CAR T cell therapy can be added as a form of relapse prevention. CAR T cell therapy can also be used to treat chemotherapy-refractory disease, where the cancer has not adequately responded to the initial chemotherapy treatment. CAR T-cell therapy is also advantageous due to its short treatment time of 2 weeks following a single infusion (4). Since it is less aggressive than other cancer therapies like chemotherapy and stem cell transplants, patients have shown improved recovery rates as well. Its classification as a “living drug” suggests that its effects persist long after the initial infusion, protecting the body against relapse (5).
While CAR T cell therapy is very effective for blood cancers, it’s important to understand the potential side effects. Unfortunately, CAR T cell therapy can over-activate the immune system, which causes cytokine release syndrome (CRS), which eventually leads to systemic inflammation (6). Symptoms of CRS include high fever, hypotension and sometimes sepsis, which leads to organ failure and even death (6). Fortunately, corticosteroids and anti-inflammatory medications can help patients recover from CRS. In addition to CRS, CAR T cell therapy can also cause “on target, off tumour” toxicity. This can be caused by the target antigen also being present in healthy tissues, leading to T cells targeting healthy tissue within the patient (6). For example, the antigen CD19 which is targeted in some CAR T cell therapy treatments, is found on malignant B cells in blood cancers and also appears on normal B cells (6). This on-target, off-tumour toxicity is also a primary challenge in the development of CAR T cell therapy for solid tumour cancers, or cancers with a localized mass.
Solid tumours usually share the same antigens that non-cancer cells also have (2). When a CAR T cell is designed to recognize a shared antigen, the CAR T cell will invariably end up attacking both cancer cells and normal cells. As well, the antigens on the surface of a solid tumour can change over time, so there often is not only one target but many shifting targets. One strategy to resolve this issue involves designing CAR T cells that can recognize multiple antigens at the same time (2). Despite having the same types of antigens that normal cells have, solid tumours can still be separated from normal cells by the unique pattern of their antigen collection. So these special CAR T cells take advantage of solid tumor antigen patterns to identify cancer cells and avoid normal cells that do not have the cancer antigen pattern.
Compared to blood cancers where scattered cancer cells can be easily accessed by CAR T cells, the solid tumour mass means that CAR T cells have to travel deep into the tumour to kill the cancer cells that are on the inside (2). On top of this barrier of access, the region around a solid tumour is filled with signals that suppress and weaken T cells. To help CAR T cells reach the tumour, researchers are looking for ways to make T cells more resistant to suppression signals. T cells can also be altered to respond to migration signals (chemokines) that the tumour produces. These altered T cells will be drawn towards migration signals found in the tumour. As a result, more T cells will migrate towards the tumour and burrow deeper inside.
Despite the challenges associated with trying to apply CAR T cell therapy for solid tumours, it remains a very attractive area of development (7). CAR T cell therapy is a viable immunotherapy that doctors can add to their library of treatments. This is especially important for cancer patients with solid tumours that do not respond well to existing treatments. Currently, research on solid tumour applications is focused on increasing targeting efficiency by changing the CAR, and improving tumour penetration by altering the T cell. As time goes on, researchers will only get better at ensuring on-site action and minimizing off-target effects. CAR T cell therapy is already much more specific than systemic cancer treatments, and with this direction of improvement, the benefit of CAR T cell therapy will only become stronger.
References
1. Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments | Journal of Translational Medicine | Full Text. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04292-3.
2. Guzman G, Reed MR, Bielamowicz K, Koss B, Rodriguez A. CAR-T Therapies in Solid Tumors: Opportunities and Challenges. Current Oncology Reports. 2023;25(5): 479–489. https://doi.org/10.1007/s11912-023-01380-x.
3. Roschewski M, Longo DL, Wilson WH. Chimeric Antigen Receptor T-cell Therapy for Large B-cell Lymphoma: Who, When, and How? The New England journal of medicine. 2022;386(7): 692–696. https://doi.org/10.1056/NEJMe2118899.
4. Advantages of CAR-T Cell Therapy | Rutgers Cancer Institute of New Jersey. https://www.cinj.org/patient-care/advantages-car-t-cell-therapy.
5. Han D, Xu Z, Zhuang Y, Ye Z, Qian Q. Current Progress in CAR-T Cell Therapy for Hematological Malignancies. Journal of Cancer. 2021;12(2): 326–334. https://doi.org/10.7150/jca.48976.
6. Adkins S. CAR T-Cell Therapy: Adverse Events and Management. Journal of the Advanced Practitioner in Oncology. 2019;10(Suppl 3): 21–28. https://doi.org/10.6004/jadpro.2019.10.4.11.7. CAR T Cells: Engineering Immune Cells to Treat Cancer – NCI. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells.
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