Immunotherapy, a Rising Star in Cancer Treatment: Part II
Abstract: What is the role of our immune system? Fight against virus and bacteria! That’s right. Do you know that our immune system also protects us against internal insults such as cancer? With the rapid development of cancer immunotherapy, we are well on our way to leverage our own immune system to fight against cancer. In Part II of this article, we will be highlighting recent advances in CAR-T cell immunotherapy and providing you our prospect of the cancer immunotherapy field.
CAR (Chimeric Antigen Receptor)-T cell immunotherapy
In the previous article, we discussed about recent advances in the development of immune checkpoint blockade therapy. One important prerequisite for this therapy is that the tumor could initially induce the immune response; therefore, the problem comes from the immune inhibition during chronic inflammation, and therapeutically we could re-activate the immune system to target tumor. However, some tumors initially fail to have or present tumor specific antigens to induce effective T cell immune response. To overcome these problems, genetically modified T cells that are engineered to target specific tumor antigens and/or genes that are involved in survival, proliferation, and the enhancement of effector functions have been under intense research. This is called “CAR-T cell immunotherapy”.
General procedure of CAR-T cell therapy
CAR technology was originally reported by Zelig Eshhar in 1993. The general procedure is: 1) Separate T cells from patient; 2) Engineer these T cells to express an artificial receptor, which is called “CAR” that usually targets tumor-specific antigen; 3) Expand the CAR T cells to a sufficient amount; 4) Re-introduce the CAR T cells to patient. There are two major components that are critical to the CAR-T cell immunotherapy: the design of CAR itself and the choice of the targeted tumor specific antigen.
Generations of CAR: Both T cell activation and survival are important
Currently, there are four generations of CAR. The first generation has only CD3ζ on its intracellular domain, and the resulting T cells were found to have very poor survival in patients. Later on, researchers realized that CAR T cells need at least 2 different signals for optimal activation and survival. This leads to the production of the second and third generation of CAR, with their intracellular tail containing 1-2 additional co-stimulatory elements (e.g. CD28) beside the original CD3ζ domain. The fourth generation of CAR is similar to the second generation except that it is able to secrete a pro-inflammatory cytokine IL-12, which could further attract innate immune cells and thus enhance the immune response.
Choice of the targeted antigen: Critical for the success of clinical trials
The choice of targeted antigen is critical for CAR-T cell therapy to be successful. Unfortunately, it is difficult to find an antigen that is specifically expressed on tumor cells as most antigens will result in undesirable targeting of normal tissues. This underlines the main toxicity effects observed in CAR-T cell therapy. It has been shown that treating a colon cancer patient with CAR therapy against ERBB2 resulted in patient death after 5 days of CAR T cell infusion, which is most likely due to the fact that ERBB2 is also expressed on normal lung epithelium.
The recent clinical success of CAR-T cell therapy comes from targeting CD19 antigen for B-cell malignancies. CD19 expression is confined to B-cells, and the toxicity due to B-cell depletion is clinically manageable. The CD19-specific CAR-T cell therapy has been shown to induce persistent remissions in patients with relapsed B-cell malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and non-Hodgkin lymphoma.
Compared to the clinical success of CD19-specific CAR-T cell therapy, finding an optimal antigen target for solid tumor falls behind. Recently, some pre-clinical studies and phase I trials showed that mesothelin, a cell-surface antigen implicated in tumor invasion, might be a potential CAR-T cell therapy target; however, further clinical trials are needed to provide further evidence.
Recent innovations that could favor the CAR-T cell-based clinical trials
The generation of CAR T cells that target different antigens is labour intensive, hence it is expensive and time-consuming to engineer T cells for individual patient, especially when multiple or sequential CAR-T cell treatments are needed. Recently, a more cost-effective anti-tag CAR system has been described. The idea is to target tumor antigens with tag-conjugated antibodies or drugs, which then can be identified by CAR T cells that are specific for that tag. This way, we can perform multiple CAR-T cell therapies with just one type of CAR T cell.
CAR-T cell immunotherapy can be dangerous or even life-threatening when a “bad” antigen is selected. To increase the safety for clinical trials, a drug-inducible suicide gene can be introduced if an adverse event occurs. This “safety-switch system” can rapidly deplete unwanted CAR T cells. This innovation could potentially improve the safety of CAR T-cell therapy and thus expand its clinical application.
Perspectives for cancer immunotherapy
Biomarker development is critical for the future success of cancer immunotherapy
Usually, only a subpopulation of cancer patients benefits from a specific immunotherapy. Therefore, if we can pre-select cancer patients based on their expected responses to a specific immunotherapy, that is, utilizing a set of biomarkers to stratify the patients for the right treatment, we can reduce the toxicity of immunotherapy, save medical resources and patients’ precious treatment time, which usually means saving patients’ lives.
Currently, considerable efforts have been dedicated to finding good biomarkers for immunotherapy. For example, PD-L1 expression on tumor cells has been shown clinically to be a useful biomarker to predict the response to PD-1/PD-L1 blockade therapy. However, 5-20% PD-L1-negative tumors were also responsive to PD-1/PD-L1 blockade therapy across different tumor types. As a result, PD-L1 expression status alone is not a sufficient biomarker for such therapy. Although, integrating immunohistochemistry and gene expression signatures is expected to improve the biomarker algorithms, we still need better predictive biomarkers for future cancer immunotherapy.
A glimpse of future cancer immunotherapy
With the rapid development of cancer immunotherapy, we predict that immunotherapy may become the first-line therapy for most cancers in the future. When a patient is diagnosed with cancer, a pathologist will first examine his or her tumor biopsy and assign an immunoscore for diagnosis and prognosis purposes. Then based on the presence of certain immuno-biomarkers, the physician will choose a specific immunotherapy-based regimen for that patient. The regimen is very likely to be a combination therapy that either combines two different immunotherapies (for example, using the immune checkpoint blockade therapy with CAR-T cell therapy to overcome the T cell exhaustion problem observed in the latter) or combines an immunotherapy with a non-immunotherapy (such as chemotherapy to better kill cancer cells, which in turn exposes more tumor antigens to boost the effects of immunotherapy). In addition, finding a supplementary drug that can lower the autoimmune side effects without significantly compromising the effects of immunotherapy might also be possible in the future. Taken together, we believe that the long-lasting effects of immunotherapy may be able to significantly improve the five-year survival rate and to increase the likelihood of curing cancer in the foreseeable future.
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