Scope of CAR-T Immunotherapy


Immunotherapy is an innovative way of treating cancer by utilizing the body’s immune system in eliminating cancer cells. It uses antibodies made in the laboratory and are administered to treat cancer patients.

Researchers are developing methods of using the immune system to combat cancer. These methods include monoclonal antibodies that target a specific antigen present at the cancer cells surface, checkpoint inhibitors, cancer vaccines, modified viruses that kill cancer cells and chimeric antigen receptor (CAR) T therapy which is an adoptive T cell therapy that uses laboratory engineered T-cells to better combat cancer cells. First, T cells are isolated from the patient’s blood and are activated. Upon isolation and activation, T cells are genetically engineered at the laboratory to express the CAR construct. The genetically engineered CAR T cells are then infused back into the patient and once the cells are in the bloodstream, CAR-T cells attack the cancer (Hartmann et al., 2017).

CAR-T therapy has already provided remarkable results in treating hematologic cancers using CD19-specific CAR T cells. This breakthrough lead to the increase CAR T cell trials that targets other B- cell antigens including CD20, CD22, CD23, ROR1 and kappa light chain (D’Aloia et al., 2018). With the remarkable results in hematologic cancer treatment, clinical trials for solid tumors are also being done focusing on solid tumor surface proteins such as interleukin 13 receptor α (IL-13Rα), human epidermal growth factor receptor 2 (HER2), fibroblast activation protein (FAP), carcinoembryonic antigen (CEA), diganglioside GD2, mesothelin and L1 cell adhesion molecule (L1 CAM) to name a few (Newick et al., 2016).

Figure 1. Target antigens for hematological malignancies.

Source: Hartmann et al., 2017

Figure 2. Antigen targets for hematologic malignancies clinical outcome. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NR, no response; NE, not evaluable.

Source: Hartmann et al., 2017

According to the study of Hartmann et al., 17 antigen targets for hematologic cancers are being studied as shown in figure 1 and out of the 17 targets only 7 have clinical outcomes as presented in figure 2. Based on the data presented, CD19 is the most targeted antigen.

Figure 3. Antigen targets for solid tumors

Source: Hartmann et al., 2017

Figure 4. Antigen targets for solid tumors clinical outcome. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NR, no response; NE, not evaluable.

Source: Hartmann et al., 2017

Figure 3 shows antigen targets for solid tumors and figure 4 presents the clinical outcome. According to the study of Hartmann et al., the previous clinical trials for solid tumors focused on CEA as target antigen for colorectal cancer, breast cancer, gastric cancer, adenocarcinoma and liver metastases. Compared with the hematologic data, solid tumors present no significant results except for GD2 which have more than 50% CR.

Figure 5. Indication, age differentiation and CAR generation

Source: Hartmann et al., 2017

Figure 5 represents the results conducted by Hartmann et al. that analyzed all available data from completed and on-going clinical trials of CAR-T cell therapy. According to their study, 113 current trials targets hematologic cancers and 78 clinical trials targets solid tumors. This data also shows the age distribution for hematologic malignancies and solid tumors (5B) as well as CAR construct generation (5C). As figure 5A shows, clinical trials for hematologic cancers are greater than solid tumors. This is for the reason that solid tumors have barriers that are absent in hematologic cancers as indicated in figure 6 together with the strategies to overcome the barriers.

Figure 6. Obstacles that hinder CAR T cells function.

Source: Newick et al., 2016

In solid tumors, CAR-T cells must traverse the blood into the solid tumor site. Once at the site they must infiltrate the stromal elements of solid tumors. Even if the CAR-T cells successfully traversed and infiltrated the tumor sites, they become dysfunctional due to the tumor environment (low pH, oxygen and nutrient content), presence of cytokines, regulatory T cells, myeloid-derived suppressor cells and tumor associated macrophages (Newick et al., 2016).

Inefficient trafficking towards the solid tumor site is one of the barriers that neutralize the function of the CAR-T cells. In Sridhar and Petroca’s review of regional delivery of CAR-T for cancer therapy, they reviewed the current status of regional delivery of the CAR-T cells in the clinical settings which has been explored by researchers to bypass the obstacle that is presented by inefficient trafficking. Sridhar and Petroca reviewed the clinical trials done by Yaghoubi et al. and Brown et al. that targets glioblastoma thru intralesion and intracranial delivery and Katz et al. that targets hepatic metastases of colorectal adenocarcinoma via hepatic artery infusions. The review presents the safety and feasibility of CAR-T cell regional delivery. Regional delivery increases efficacy of CAR-T cells by bypassing the trafficking and tumor microenvironment barrier but several limitations still exist.

Clinical trials of CAR-T cell therapy for hematological malignancies shows huge success compared to clinical trials for solid tumors because of the barriers present with. By pooling all the data and information from the success of CAR-T therapy in hematologic cancer and with the researches done to bypass the barriers for solid tumors, CAR-T cell therapy for solid tumors can catch up with hematologic cancer’s the level of success.


References:

D’Aloia, M. M., Zizzari, I. G., Sacchetti, B., Pierelli, L., & Alimandi, M. (2018). CAR-T cells: The long and winding road to solid tumors review-article. Cell Death and Disease, 9(3). https://doi.org/10.1038/s41419-018-0278-6

Hartmann, J., Schüßler‐Lenz, M., Bondanza, A., & Buchholz, C. J. (2017). Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts. EMBO Molecular Medicine, e201607485. https://doi.org/10.15252/emmm.201607485

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. https://doi.org/10.1146/annurev-med-062315-120245

Sridhar, P., & Petrocca, F. (2017). Regional delivery of chimeric antigen receptor (CAR) T-cells for cancer therapy. Cancers, 9(7), 1–10. https://doi.org/10.3390/cancers9070092

Tice, J., Walsh, J., & Chapman, R. (2017). Chimeric Antigen Receptor T -Cell Therapy for B - Cell Cancers: Effectiveness and Value. Retrieved from https://icer-review.org/wp-content/uploads/2017/07/ICER_CAR_T_Draft_Evidence_Report_121917.pdf