Neoantigen-based cancer immunotherapy

“Cancer immunotherapy is a therapy used to treat cancer patients that involves or uses components of the immune system. Some cancer immunotherapies consist of antibodies that bind to, and inhibit the function of, proteins expressed by cancer cells. Other cancer immunotherapies include vaccines and T cell infusions.”— Nature.com

The 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation. It’s not an overnight success, as harnessing the immune system to eliminate tumors have been under development since the start of 20th century. Several effective strategies emerged over the past decade are now widely considered as promising tools for the treatment of cancers. CAR-T cell therapy and immune checkpoint blockade (CPB) have been shown effective in clinical trials.  Nevertheless, both CAR-T and CPB have limitations. The CAR-T approach could not work well for solid tumors, and the objective response rate of CPB is limited in most tumor types. Therefore, only a small population of patients could benefit from these therapy approaches. Increasing research then focused on understanding the biological basis, identifying which patients are likely respond or not respond to the therapies, and how to increase the effectiveness. A rational approach is to combine checkpoint blockade therapy with personalized neoantigen vaccines. 

Fig. 7 Blocking PD-1 or PD-L1 allows T cell killing the tumor cell. Source: National Cancer Institute

On the other hand, the inhibitory signals present in the tumor environment could prevent T-cells from being activated, expanded, or infiltrating the tumor. Studies also shown that tumor vaccines could stimulate the patient’s immune system while also improve the immunosuppressant effect. Comparative studies have shown that the combination of neoantigen-based vaccine and checkpoint blockade therapy could result in a higher rate of efficacy. 
Traditional treatments such as radiotherapy and chemotherapy can also enhance the role of neoantigen vaccines, by inducing tumor cells to release more antigens, enhancing the transport of T cells into tumor tissue, enhancing the anti-tumor response, or reducing the immune suppression [1]. Neoantigen-based adoptive cell transfer (ACT) treatment is an alternative to neoantigen vaccines. Instead of developing a vaccine, some groups have shifted to focus on engineering T cells that recognize tumor neoantigens and then can be infused into the patient. Though neoantigen vaccines alone could not completely eliminate the malignant tumors, they produce stronger antitumor response when combined with other therapies.

Fig. 8 Combination of neoantigen vaccines with other therapies [1].

The encouraging results from preclinical studies accelerated the development of clinical trials of neoantigen-based vaccines and therapies. The first human clinical trial using a neoantigen vaccine published its results in 2015 [9]. Soon later, in 2017, two significant studies published by Ott et al. and Sahin et al. confirmed the efficacy of neoantigen vaccines treating melanoma in humans [17, 18]. Apart from melanoma, recently studies have expanded the application of to neoantigen-based cancer vaccines to various types of cancers, including human glioblastoma, pancreatic tumor, kidney cancer, lung cancer, prostate cancer and so on. Preliminary studies of neoantigen-based adoptive cell transfer (ACT) treatment also showed promising results. 

Current clinical trials of neoantigen-based cancer vaccines and cell therapy.pdf
As the data shows, emerging clinical trials are submitted in the recent years and most of them are located in the United States, Europe and China. Neoantigen plays a critical role in antitumor immune response and cancer immunotherapies. Both neoantigen-based vaccine and adoptive cell transfer (ACT) therapies show promising effects in previous studies. Combination of neoantigen with other immune therapies, such as checkpoint blockade, and conventional treatments such as chemo/radio therapy are under assessment. While the scientists are working on exploring more neoantigens and methods to work best in different patients and tumors, pharmaceutical companies have already marked their territory by transferring research advance into medical treatments. 

Related articles

Chapter 1: What are neoantigens and how to identify them?

Chapter 2: Personalized neoantigen vaccines

Chapter 4: Key players in the neoantigen industry

References

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