Difference between revisions of "Team:Tongji China/Neoantigen"

The treatment for cancer has undergone evolutionary changes as an understanding of the underlying biological processes has increased. Tumor removal surgeries have been documented in ancient Egypt, while hormone therapy and radiation therapy were developed in the late 19th Century. Chemotherapy, immunotherapy and newer targeted therapies are products of the 20th century. As new information about the biology of cancer emerges, treatments will be developed and modified to increase effectiveness, precision, survivability, and quality of patients' life.[1]

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Radiation therapy

Chemotherapy

Targeted therapy

Immunotherapy

Cancer immunotherapy enlists and strengthens the power of a patient's immune system to attack tumors. Four verified methods in terms of immunotherapy are cellular immunotherapy (such as dendritic cell therapy, CAR-T therapy and TIL therapy), cytokine therapy (interferon and interleukin), monoclonal antibody therapy and checkpoint inhibitors (such as CTLA-4 blockade and PD-1/PD-L1 inhibitors). They have made full acquaintance with the public by their high performance in curing people of several types of cancers and, before long, James P. Allison and Tasuku Honjo are bestowed with 2018's Nobel Prize in Physiology or Medicine for their work on CTLA-4 and PD-1/PD-L1 inhibitors. Compared with previous treatments for cancer, immunotherapy is marked by its capacity to significantly prolong the patients' survival time as well as remaining effectiveness even in advanced cancer stages.[1][2]

Neoantigen vaccine

Here comes the little child of immunotherapy: Neoantigen vaccine. It is born for the future while returning to the most essential fact that tumor is the outcome of tumor-specific mutations.
Some of the mutations are driver mutations (carcinogenic mutations). Others, which were regarded as a nonentity in the past, have recently shown great potential in dealing with cancer. These "byproducts" let tumor cells express antigenic peptides (epitopes) that can be recognized by autologous tumor-specific T cells and that enhancement of such immune reactivity can possibly lead to cancer control and cancer regression in patients with advanced disease. Unlike driver mutations which are conservative, sub-mutations are highly diverse, varying from person to person. Epitopes arising from these individual tumor-specific mutations are the so-called "neoantigens". Neoantigens have two significant features: First, it is unique to cancer cells which normal tissues and cells do not have. Second, these abnormal proteins can be recognized by the immune system and activate immune cells. At present, the academic community estimates that the tumors of most patients should be able to find more or less neoantigens.[3] From the picture shown above (Figure 1), we can indicate that some tumors hold heavy TMB, especially the bladder cancer, melanoma, colorectal cancer and the non-small cell lung cancer. By training the immune system with synthetic neoantigen vaccines, researchers hope to selectively eradicate the cancer cells while leaving healthy tissue unharmed.

It has been demonstrated by preliminary clinical trials that neoantigens do make sense in cancer control. Carreno et al. (2015) were the first to report that neoantigen-pulsed DC can induce neoantigen-specific T-cell responses in melanoma patients. Two years later, Patrick A. Ott et al. and Sahin et al. (2017) confirmed the potential of neoantigen vaccines in treating melanoma patients and expanded the repertoire of neoantigen-specific T cells. Moreover, it is encouraging that adverse events observed within these trials are mild and relatively innocuous.[4][5]
Although clinical research concerning this newly-designed cancer therapy is so far inadequate, one thing virtually for sure is the workflow of a neoantigen vaccine (as is shown in the figure below):
 1. Get the comprehensive mutational spectrum of individual tumors (i.e., the "mutanome") by means of deep sequencing.
 2. Pick out possible "neoantigens" from the mutanome with help of bioinformatic prediction.
 3. Synthesize selected "neoantigens" in vitro and vaccinate the candidate patient, whose immune system will then be stimulated to generate adaptive immune responses targeting the “neoantigens” infused.
 4. Therapeutic immunization occurs to recognize and attack cancer cells expressing epitopes the same as "neoantigens".

The only challenge here is how to decide on "neoantigens" among tons of candidate peptides. It is already known that endogenic tumor-specific antigens are presented to T cells by MHC class I molecules (HLA-I). So the point is converted to predicting peptides' binding affinity to HLA-I. This is really a technical problem, because of not only algorithm development but also the abundant diversity of HLA-I genotypes between individuals. The up-to-date and most widely-accepted computational tool to predict neoantigens is NetMHC Server (www.cbs.dtu.dk/services/NetMHC) exploited by DTU Bioinformatics. However, there's still lifting space for its accuracy and speed.[6]

In the post-genome era, the mutanome holds promise as a long-awaited 'gold mine' for the discovery of distinct neoantigens, which are exclusively tumor-specific and unlikely to induce immune tolerance, hence offering the chance for highly promising clinical programs of cancer immunotherapy. It can be foreseen that with further maturation of sequencing technology and in silico predictive strategies, a painless and costless neoantigen vaccine therapy will be available someday in the near future, for the human being and a better world.


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