“CARTing” away solid cancerous tumors!

Chimeric Antigen Receptors are surprisingly not related to mythological creatures that are part lion, goat, and snake. More excitingly, they are engineered receptors that can bind to specific antigens on cancer cells, allowing them to be identified and lysed. T-cells can be genetically modified to produce CAR receptors, creating a promising and effective therapy that can treat various cancers. 

Currently, CAR t-cell therapies are specialized to the patient, as they require t-cells to be taken from the patient and genetically modified to produce CAR receptors. The CAR t-cells are multiplied in a lab environment before being infused into the patient. They continue to multiply, in the bloodstream, as they identify and lyse cancer cells, with the help of cytokines. Despite the exciting nature of CAR t-cells, this treatment has led to long-term survival for less than half of its patients and has a number of limitations and side effects. The mass influx of t-cells entering the bloodstream causes hormonal and cellular imbalances, leading to Cytokine Release Syndrome. CRS can be treated and kept at bay, depending on its severity, and is ironically a sign that the CART therapy is doing its job. Another limitation is that the CAR t-cells are infused into the patient’s blood, and are therefore limited to only treating blood cancers. 

There are multiple barriers preventing CART therapy to be applicable to solid tumors, not solely physical ones such as not being able to reach the tumor. Immune-suppressing molecules, part of the microenvironment surrounding the tumor, could attack, suppress, or hinder CAR t-cells, stopping them from doing their duty or even causing them to malfunction. Solid cancer types are also heavily varied, and even the same cancer type can be vastly molecularly different from patient to patient. It is also hard to identify specific antigens that are only present on cancer cells, and not a multitude of other, healthy, cells. However insurmountable these obstacles seem, there are labs that are trying to address them. 

For example, Appel Lab at Stanford is developing a hydrogel to contain the CAR t-cells, along with cytokines to promote multiplication and immune activity, and will be directly injected into the tumor site. The gel provides an environment where the CAR t-cells can multiply and “prepare to fight cancerous cells”. The gel slowly releases the t-cells over time, allowing the tumor to be constantly attacked.

To address the immune-suppressing molecules in the tumor’s surrounding microenvironment, researchers are developing “armored” CAR t-cells. Engineering the t-cells to excrete certain proteins and hormones combats inhibitory molecules, thereby allowing the t-cells to work efficiently without malfunctions. 

Solid tumors heavily vary amongst patients, making generalized treatment for a group of patients a lofty goal. However, researchers are working on identifying specific antigens present on the surface of certain solid tumors, allowing CART work to progress for these specific cancers. Some antigens identified are the GD2 receptor, present on a type of brain cancer called DIPG, and the tMUC1 receptor present on triple-negative breast cancer (TNBC) cells. Another promising target for CART cells, specifically for treating TNBC, is mesothelin, a glycoprotein expressed on mesothelial cells. Exploring new antigens to target is crucial in the progression of CART therapies, as all other modifications made to CAR t-cells will be futile if the cells don’t have a proper target. 

CART therapies are rapidly advancing and improving, both in their efficacy along with their accessibility. 6 CAR t-cell therapies have currently been approved by the FDA for the long-term treatment of blood cancers. However, to take these treatments to the next level, researchers are working to make them cheaper and more available to the general populace. One take on this issue is to use t-cells from a general pool of healthy donors, as opposed to taking the t-cells directly from the patient. Although using t-cells directly from the patient makes the treatment individualized, using general t-cells and specializing them to the tumor can make CART therapies infinitely more accessible and cheaper. This new approach could lead to CART treatments becoming the standard treatment option for certain cancers, overtaking radiation and chemotherapy. It is the hope that CART therapies will eventually become “off-the-shelf” treatments, being immediately available for use. 

As of now, CAR t-cells are considered an alternative, in the case that a patient’s cancer has worsened despite the use of other treatments. Nonetheless, CART therapies have the potential to revolutionize the cancer treatment field, and are a promising option for less invasive, effective treatments. As their adaptability and efficacy continue to improve, the prospect of beating cancer, without going through the pain of radiation and chemotherapy, becomes within reach. 

References

Batlevi, CL, et al. “PHASE I CLINICAL TRIAL OF CD19-TARGETED 19-28Z/4-1BBL ‘ARMORED’ CAR T CELLS IN PATIENTS WITH RELAPSED OR REFRACTORY NHL AND CLL INCLUDING RICHTER TRANSFORMATION.” Hematological Oncology, vol. 37, no. S2, June 2019, pp. 166-67, https://doi.org/10.1002/hon.124_2629.

“Cancer Cells”. 2021. Froedtert Hospital, https://www.froedtert.com/sites/default/files/styles/story_hero_medium/public/image/2022-04/cancer-general.webp?itok=yoYou2Kh

“CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers.” National Cancer Institute, U.S. Government, 10 Mar. 2022, www.cancer.gov/about-cancer/treatment/research/car-t-cells.

Marofi, F., et al. “CAR T cells in solid tumors: challenges and opportunities.” Stem Cell Res. Ther., vol. 12, https://doi.org/10.1186/s13287-020-02128-1.

Stanford University. “Stanford Engineers Enhance the ‘Attack Power’ of Cutting-Edge Cancer Treatment.” SciTech Daily, 8 Apr. 2022, scitechdaily.com/stanford-engineers-enhance-the-attack-power-of-cutting-edge-cancer-treatment/.

Tchou, J., et al. “Mesothelin, a novel immunotherapy target for triple negative breast cancer.” Breast Cancer Res. Trea., vol. 133, nos. June 2012, Mar. 2012, pp. 799-804, https://doi.org/10.1007/s10549-012-2018-4.

Zhou, Ru, et al. “CAR T Cells Targeting the Tumor MUC1 Glycoprotein Reduce Triple-Negative Breast Cancer Growth.” Front. Immunol., vol. 10, no. 2019, https://doi.org/10.3389/fimmu.2019.01149. Accessed 24 May 2019.