Sending T-cells, the Soldiers of Our Body’s Immune System, to Fight Against Cancer

Written by Tonya Mukherjee and Edited by Catherine Zhang

As of August 2017, a new cancer treatment has been made available for clinical use. Chimeric Antigen Receptor T cells are genetically modified immune cells, which are created to bind to and destroy cancer cells by recognizing their unique surface proteins [1]. CAR-T cell therapy is a unique cancer treatment that utilizes genetic modification to program immune cells to fight cancer cells [2]. Clinical trials show that these immune cells can be deployed to treat different cancers with overwhelmingly positive results [3]. 

The development of cancer immunotherapy has a long history: originally, the first-ever immunotherapy drugs were made available in 1997. Immunotherapy drugs utilize specific antibodies to bind to tumor cells and signal immune cells to destroy them [4]. Although immunotherapy drugs are still popular, they have only shown positive results in select cancer patients. Also, patients often develop drug resistance, so their treatment effects weaken over time. Thus, while cancer remains incurable, scientists continue to develop new methods to treat it, and as of 2017, CAR-T cell therapy has become one such option to be made public  [5]. 

The first-ever FDA approved CAR-T cell therapy was utilized in August 2017 to treat childhood acute lymphoblastic leukemia (ALL) [2]. White blood cells play an important role in the immune system, but in all patients, too many immature white blood cells are made, and thus they become cancerous. Since most cancer immunotherapies rely on stimulating the immune system into attacking cancer cells, auto-immune cancers are especially difficult to tend; thus, the development of CAR-T cell therapy provides an alternative treatment for patients who do not respond to general cancer immunotherapy procedures [3].

The most unique aspect of CAR-T cell therapy is that immune cells can be genetically modified to treat specific types of cancer. For example, in 2017, scientists genetically modified immune cells to treat neuroblastoma, a cancer most commonly found in infants, and small-cell lung cancer, a cancer typically found in smokers. Although clinical trials with these unique CAR-T cells are still underway, lab tests show positive results [1]. Compared to other cancer treatment methods, CAR-T cell therapy has already been proven to have a significantly lower relapse rate, better long-term results, and a higher cancer cell destruction rate of 70-90% in both adult and child leukemia patients  [3]. Similarly, immune cell therapy specific to cancers such as neuroblastoma and small-cell lung cancer has been equally effective in lab testing [6]. 

Despite its many positive results, however, cancer immune cell therapy unfortunately also has negative side effects. Although cases are few, neuroblastoma and small-cell lung cancer models have shown that different CAR-T cells specific to different cancers will attack each other, therefore suggesting that only one type of immune cell can be utilized to treat one type of cancer [1]. In rare cases, patients develop auto-immune diseases such as B cell aphasia. B cell aphasia is an auto-immune disease in which CAR-T cells kill normal lymphocytes that express surface proteins similar to cancerous ones. Another problem with CAR-T cell therapy is that, if cancer relapses, cancer cells may express fewer of the surface proteins which immune cells must locate, and so its effectiveness can diminish [3]. CAR-T cell therapy can also cause cytokine release syndrome (CRS), which is a toxic inflammatory response caused by excess immune system signaling. CAR-T cell therapy’s side effects are rare and can usually be treated; however, in some cases, they can also be lethal [2]. 

References:

1. Crossland, D.L., Denning, W.L., Ang, S., Olivares, S., Mi, T., Switzer, K., Singh, H., Huls, H., Gold, K.S., Glisson, B.S., Cooper, L.J., Heymach, J.V., (2018). Antitumor activity of CD56-chimeric antigen receptor T cells in neuroblastoma and SCLC models. Oncogene, 37: 3686-3697.
2. National Cancer Institute, “CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers.” Cancer.gov, National Cancer Institute, 30 July. 2019. Retrieved from https://www.cancer.gov/about-cancer/treatment/research/car-t-cells 
3. Fry, T. J., Shah, N. N., Orentas, R. J., Stetler-Stevenson, M., Yuan, C., M., Ramakrishna, S., Wolters, P., Martin, S., Delbrook, C., Yates, B., Shalabi, H., Fountaine, T. J., Shern, J. F., Majzner, R. G., Stroncek, D. F., Sabatino, M., Feng, Y., Dimitrov, D. S., Zhang, L., Nguyen, S., Qin, H., Dropulic, B., Lee, D. W., Mackall, C. L., (2017). CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nature Medicine, 24: 20-28. 
4. Ventola, C.L., (2017). Cancer Immunotherapy, Part 3: Challenges and Future Trends. Pharmacy and Therapeutics, 42: 514-521
5. What is biotechnology? “Cancer Immunotherapy.” whatisbiotechnology.org, The Biotechnology and Medicine Education Trust, n.d. Retrieved from https://www.whatisbiotechnology.org/index.php/science/summary/cancer-immunotherapy/
6. Smith, E.L., Staehr, M., Masakayan, R., Tatake, I.J., Purdon, T.J., Wang, X., Wang, P., Liu, H., Xu, Y., Garrett-Thomson, S.C., Almo, S.C., Riviere, I., Liu, C., Brentjens, R.J., (2018). Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector. Molecular Therapy, 26: 1447-1456