Immunotherapy is emerging as a powerful weapon in fighting cancer by restarting and maintaining the cancer-immunity cycle to identify, control and eliminate tumor cells rather than killing them directly.
Cancer is a significant public health problem worldwide and one of the most common causes of death in China, with annual relevant medical expenditure exceeding CNY 220 billion (USD 30.72 billion), according to the data revealed by the National Cancer Center (NCC) in 2019. There were 4.57 million new cancer cases and 3 million deaths in China in 2020, accounting for 23.7% and 30% of total cases worldwide.
What's the first approach that comes to your mind when mentioning cancer treatment? Surgery, radiotherapy or chemotherapy? These are indeed the most conventional measures for cancer treatment. However, immunotherapy is emerging as one of the most promising directions in cancer treatment.
The market for immuno-oncology drugs in China has multiplied in recent years. According to Frost & Sullivan, the Chinese immuno-oncology drug market has increased from CNY 685 million to CNY 17.12 billion from 2017 to 2021, with a CAGR of 110.5%. The global market is expected to reach CNY 348.70 billion in 2022, with the Chinese market accounting for 6.09%.
What is immunotherapy?
Under normal circumstances, the body can recognize and eliminate cancer cells in the tumor microenvironment through the cancer-immunity cycle.
However, cancer cells can employ different strategies to suppress the body's immune system so that it fails to kill tumor cells regularly, thus surviving all stages of the immune response to the tumor, known as the immune escape.
Immunotherapy is a form of cancer treatment to control and eliminate tumors by restarting and maintaining the cancer-immunity cycle and restoring the body's normal anti-cancer immune response. It comes in various forms, including immune checkpoint inhibitors, adoptive cell transfer (ACT), cancer vaccines, and oncolytic viruses. Immune checkpoint inhibitors and adoptive cell transfer have witnessed the most rapid development.
Immune checkpoint inhibitors
Immune checkpoint molecules are critical modulators of the anti-tumor T cell immune response presented mainly on T cells, antigen-presenting cells (APCs) and tumor cells. Their interaction activates either inhibitory or activating immune signaling pathways. Inhibitory immune checkpoints play a crucial role in maintaining immune self-tolerance, acting like the brakes on an automobile to prevent T cells from displaying autoimmune reactions. Cunning cancer cells can exploit this mechanism to put the 'brakes' on the immune system attack.
Immune checkpoint inhibitors prevent inhibitory immune checkpoints from binding to ligands on tumors, releasing the 'brakes' and reactivating immune cells. Cytotoxic T lymphocyte antigen-4 (CTLA-4, also known as CD152), programmed cell death protein-1 (PD-1, also known as CD279) and programmed cell death ligand-1 (PD-L1, also known as CD274) are the most famous inhibitory immune checkpoints currently.
Ipilimumab, an anti-CTLA-4 antibody for metastatic melanoma, was the first immune checkpoint inhibitor drug to be listed. In 2014, the first PD-1 monoclonal antibody was approved for the treatment of advanced melanoma, followed by several immune checkpoint inhibitors for other indications, opening the door to cancer immunotherapy.
According to PharmSnap, 22 monoclonal antibody drugs targeting PD-1, PD-L1 and CTLA-4 have been approved worldwide by November 2022, with PD-1 and PD-L1 accounting for more than 90%. And China has been a leader worldwide in immune checkpoint inhibitors, with 50% of the 22 approved monoclonal antibody drugs initially developed by Chinese companies.
Chinese companies focusing on immune checkpoint inhibitors include Akeso (Chinese：康方生物), Junshi Biosciences (Chinese：君实生物), Henlius (Chinese：复宏汉霖), Innovent (Chinese：信达生物), Lepu Biopharma (Chinese：乐普生物) and Hengrui Pharmaceuticals (Chinese：恒瑞医药).
Adoptive cell transfer
Adoptive cell transfer (ACT) therapy transfers immunocompetent cells into the body after they are modified and augmented to possess more effective anti-pathology features to kill cancer cells or stimulate the immune response to kill the tumor indirectly.
Chimeric antigen receptor (CAR) T-cell therapy dominates the ACT immunotherapy market, where autologous T-cells are genetically engineered to express CARs to kill the tumor cells specifically. CAR is a kind of protein receptor that enables T cells to attack tumor cells by recognizing the particular antigen on the surface of the tumor. CAR T cells are activated after binding to specific antigens, kill tumor cells by releasing substances such as perforin, and recruit endogenous immune cells to kill tumors by releasing cytokines. CAR T-cell therapy is currently most applied to hematological tumors, but its efficacy is less significant for solid tumors.
So far, eight CAR T cell products have been approved worldwide, including six FDA-approved and two NMPA-approved CAR T cell products. It is worth noting that all approved CAR T cell products are autologous. However, T cells in some patients are unhealthy after multiple lines of treatment, resulting in a tiny percentage of patients who can modify their CAR structure. Scientists are studying to broaden the source of T cells, trying to extract healthy T cells from healthy people for transformation.
Famous companies focusing on CAR T cell therapy include Novartis (Chinese：诺华), Bristol-Myers Squibb (Chinese：百时美施贵宝), Fosun Kite (Chinese：复星凯特), JW Therapeutics (Chinese：药明巨诺), Legend Biotech (Chinese：传奇生物) and Johnson & Johnson (Chinese: 强生).
Cancer vaccines can be divided into preventive cancer vaccines and therapeutic cancer vaccines. As the name suggests, preventive cancer vaccines protect against the viruses that cause tumors, reducing cancer risk in healthy people. Unlike preventive cancer vaccines, therapeutic cancer vaccines are designed to be used in patients who already have cancer—they work against cancer cells through target tumor antigens and amplify anti-tumor immune responses.
Therapeutic cancer vaccines have become a breakthrough in treating solid tumors due to their high specificity to attack tumors. Several tumor antigen forms exist, including peptides/proteins, nucleic acids, and dendritic cells (DC).
The peptide-based therapeutic cancer vaccines have attracted enormous attention in recent years. Most peptide-based vaccines are based on epitope peptides stimulating CD8+ T cells or CD4+ T helper cells to target tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs).
Nucleic acid-based vaccines, including DNA and mRNA vaccines, are plasmid vectors containing encoded protein genes introduced into the host body, enabling the host cell to express the antigenic protein to induce an immune response against the antigenic protein.
Dendritic cells (DC) are specialized immune cells that promote an immune response against antigens, including foreign pathogenic antigens and self-tumor antigens. Tumor-specific DC cells induced or constructed in vitro can be infused back into the body to activate an immune response of T cells against the tumor, which is the DC-based vaccine.
BioNTech, MSD (Chinese：默沙东), YS Biopharma (Chinese：依生生物), Likang Life Sciences (Chinese：立康生命科技) and Stemirna Therapeutics (Chinese：斯微生物) are some of the leading companies in cancer vaccines.
Oncolytic viruses (OVs) are natural or genetically modified viruses that selectively infect and replicate in large quantities to dissolve tumor cells while sparing normal ones eventually.
OVs are from diverse families of viruses, but naturally occurring OVs have been genetically engineered due to their limitations in therapeutic application. These engineered OVs with enhanced tumor targeting ability, oncolytic activity, or generating potent anti-tumor immune responses are tested in preclinical animal models and cancer patients in clinical trials. Due to their multi-mechanistic anti-tumor effects, OVs have emerged as one of the vital cancer immunotherapy agents. However, combination therapies with OVs should be tested due to the limited success of single OVs therapy.
Well-known players in the oncolytic virus field include Latima, Sunway Biotech (Chinese：三维生物), Amgen (Chinese：安进), ImmVira (Chinese：亦诺微医药) and Daiichi-Sankyo (Chinese：第一三共).
Immunotherapy is expected to change the status of cancer treatment thoroughly. North America is expected to hold a significant share of cancer immunotherapy, and the Asia-Pacific market is expected to experience the fastest growth. Chinese enterprises' innovative performance in the immunotherapy arena is gaining increasing attention worldwide. Professor Fan Guohuang, the founder of Immunophage, is optimistic about the future of the innovative drug market in China.
"China has excellent advantages in innovation policy, capital market, clinical resources and talents. Looking forward to the future, I believe the golden age of innovative medicines will come in China." Professor Fan Guohuang told EqualOcean.
We, EqualOcean, also anticipate the advent of more effective immunotherapy drugs to bring new life to more cancer patients.