Research progress in clinical efficacy evaluation of tumor immunotherapy

Xiao-Hui LiuTianjin Medical University Cancer Institute and Hospital, National Clinical Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.

Abstract Tumor immunotherapy has been a research hotspot in the field of tumor therapy in recent years, especially the successful development and application of immune checkpoint inhibitors, which has brought tumor immunotherapy into a new era. Unlike conventional treatment methods, such as chemotherapy, radiotherapy, and targeted therapy which directly affect tumor cells, immune checkpoint inhibitors block tumor immune environment checkpoint pathways and stimulate tumor-specific T cell functions to achieve anti-tumor effects. However, the clinical efficacy evaluation of immune checkpoint blockers still faces many challenges, and the solid tumor evaluation criteria(response evaluation criteria in solid tumors, RECIST) applicable to traditional chemotherapy drugs cannot accurately assess the efficacy of immunotherapy. Immune-related response criteria need further research.

Keywords: Tumor, Immunotherapy, Immune checkpoint blockers, Efficacy evaluation

Background

With the rapid increase in the incidence and mortality of tumors worldwide, malignant tumors have seriously threatened human health. Tumors are expected to be the leading cause of death in the 21st century [1]. In 2018, there were 18.1 million new tumor patients worldwide, and 9.6 million people died of malignant tumors. Among them, lung cancer is the most common tumor and the leading cause of tumor death. The 5-year survival rate of patients with advanced lung cancer is less than 5% [2].

Tumor immunotherapy can regulate the immune system and enhance the anti-tumor immune response.In recent years, significant progress has been made in the treatment of immune checkpoint blockers, and it has become an emerging tumor treatment method following surgery, radiotherapy and chemotherapy.Among them, immune checkpoint blockers represented by cytotoxic T lymphocyte-associated antigen-4(CTLA-4) and programmed death receptor-1 (PD-1)monoclonal antibodies are rapidly developing in the field of tumor immunotherapy, and are widely used in tumors such as malignant melanoma, lung cancer, and colorectal cancer, which significantly prolong the survival of patients. Some drugs acting on the immune checkpoint blockers CTLA-4 and PD-1 have shown significant clinical efficacy in a variety of tumors, and their indications continue to expand, even as first-line treatment for advanced patients [3]. Immunotherapy shows a wide range of application prospects, but it also shows certain limitations in the clinical application process. The evaluation criteria for the efficacy of tumor immunotherapy need to be further studied.

The role of the immune system in tumors

The immune system has a mechanism to recognize and clear tumor cells, which can inhibit tumor growth,invasion and metastasis, and prevent tumor progression by activating the immune response to tumor antigens.However, a variety of factors can cause immune cells to lose control of tumor cells, resulting in continued tumor growth. Such as the follow factors: (1) changes in tumor cell autoantigenicity and immunogenicity; (2)tumor cells release cytokines, chemokines and other inflammatory mediators and exosomes; (3) changes in the metabolic mode of tumor cells lead to immunosuppression of T cells; (4) expression of inhibitory ligands on the surface of tumor cells; (5)secretion of tumor-associated fibroblast immunosuppressive factors in the tumor microenvironment [4, 5]. The state of basic immune function and the composition of the intestinal flora can also affect the development of tumors [6, 7].

Tumor immune escape plays an important role in tumor development. T cell-mediated cellular immune response is the most important anti-tumor immune response, but the anti-tumor effect can only be achieved after the initial T cell activation, and T cell activation is regulated by various checkpoints. This inhibitory signaling pathway is called an immune checkpoint. The most important part of immunotherapy is to suppress the inhibitory signaling pathway of T cell activation. CTLA-4 and PD-1 and their major ligands PD-L1 are represented [8, 9]. PD-1 plays an important role in maintaining the body's autoimmune tolerance and preventing autoimmune diseases [10, 11]. Tumor cells can inhibit the function of immune cells by up-regulating the expression of PD-1 and its ligands, leading to tumor immune escape[12]. The discovery of CTLA-4 and PD-1 immune checkpoints is essential for the development of tumor immunotherapy. Mice lacking immune checkpoints CTLA-4 or PD-1 develop autoimmune diseases, and blocking CTLA-4 and PD-1 can promote antitumor immune responses [12].

The related tumor immunotherapy drugs currently developed are anti-CTLA-4 monoclonal antibodies,which can restore the T cell activation and recognition ability by canceling T cell activation inhibitory signals.Anti-PD-1 monoclonal antibody enhances the immune response by promoting the proliferation of activated T cells and activating the killing function of tumor antigen-specific cytotoxic T cells, thereby killing tumor cells. With the emergence of immunotherapeutic methods represented by immune checkpoint blockers and their survival benefits for tumor patients [13],immunotherapy has quickly attracted people's attention and has had a huge impact on the comprehensive tumor treatment model [14]. Immunotherapy has completely changed the status of tumor treatment and caused a change in the mode of tumor treatment [15].Since 2011, a variety of immune checkpoint inhibitors have been approved by the FDA for tumor treatment,such as the PD-1 inhibitors nivolumab and pembrolizumab, and the CTLA-4 inhibitor ipilimumab[16].

Efficacy characteristics of tumor immunotherapy

Currently, the most commonly used criteria for traditional radiotherapy and chemotherapy are the WHO standard [17] and the response evaluation on criteria in solid tumors (RECIST) [18]. Both were evaluated based on changes in tumor size and shrinkage of the lesion. However, unlike the cytotoxic effects of traditional therapies, tumor immunotherapy mainly suppresses tumor immune escape and induces specific immune responses to produce antitumor effects. Its clinical mechanisms of anti-tumor action are significantly different from traditional treatments such as radiotherapy and chemotherapy [19].

The process of tumor immunotherapy has a "delayeffect", that is, it takes a certain time for the immune system to recruit lymphocytes into tumor tissues and initiate anti-tumor immunity. Therefore, the efficacy of tumor immunotherapy appeared later than chemotherapy, and sometimes the improvement of the disease can be observed in patients who have been identified as PD after continuing to receive immunotherapy [20]. During the treatment process, a large number of immune cells need to be generated and infiltrated into the tumor parenchyma through the process of recruitment and proliferation to play its role.Therefore, in the early stage of treatment, the change of the tumor is often not obvious and even has an increasing trend, which causes the "false progress" of the disease. If the traditional evaluation standards are followed, the treatment effect will be wrongly estimated or the treatment will be mistakenly considered to be ineffective and the immunotherapy will be interrupted. Therefore, traditional treatment evaluation criteria are not completely applicable to tumor immunotherapy. Based on the characteristics of the efficacy of immune checkpoint inhibitors different from traditional chemotherapeutic drugs, it is necessary to find a more reasonable standard for evaluating efficacy.

Evaluation criteria for clinical efficacy of tumor immunotherapy

In 2009, immune-related response criteria were published. According to the revised WHO standard, the sum of the product of the longest vertical diameter of the tumor lesion is used to incorporate the measurable new lesion into the total tumor burden, and the change between the total tumor burden and the baseline burden is evaluated for efficacy. And the confirmation of CR, PR, and PD requires repeated evaluation at least 4 weeks apart to confirm [21]. A clinical trial found that the observed differences in survival between different groups confirm that immune-related response criteria improves patient treatment benefits, and RECIST version 1.1 underestimates the benefit of pembrolizumab in approximately 15% of patients [22].More clinical studies need to be carried out to clarify the role of immune-related response criteria in evaluating the efficacy of immunotherapy tumors.

Summary

Immunotherapy is a major breakthrough in the field of tumor therapy, and it will play an increasingly important clinical value in tumor therapy. However,the clinical mechanism of immunotherapy is significantly different from traditional radiochemotherapy. Traditional efficacy evaluation criteria are not completely applicable to tumor immunotherapy. The application of immune-related efficacy assessment criteria in clinical practice needs more research. It is believed that with the increasing application of immunotherapy, we will certainly be able to obtain feasible standardized efficacy evaluation standards in the near future.