Team:Tongji China/Neoantigen
Background
Neoantigen
return to the Background Overview
The treatment of cancer has undergone evolutionary changes as an understanding of the underlying biological processes has increased. Tumor removal surgeries have been documented in ancient Egypt, 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 life.
Surgery
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.
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”. 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.
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 is then 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, not only because of 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.
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.
References
Bobisse S, Foukas PG, Coukos G, Harari A. Neoantigen-based cancer immunotherapy. Ann Transl Med 2016;4(14):262. doi: 10.21037/atm.2016.06.17
L Li, S P Goedegebuure, W E Gillanders; Preclinical and clinical development of neoantigen vaccines, Annals of Oncology, Volume 28, Issue suppl_12, 1 December 2017, Pages xii11–xii17
NIH>National Cancer Institute
Ott PA , Hu Z, Keskin DB et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 2017; 547(7662): 217–221.
Sahin U , Derhovanessian E, Miller M et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 2017; 547(7662): 222–226.
Treatment for cancer——Wikipedia
Merits:
It can eradicate solid tumors in early stages by only one operation.
It is a local treatment with the minimal effect on the rest of the body and relatively slighter side effects.
Demerits:
It is of little help for hematological cancers (like leukemia) or metastasized ones.
There’s a risk for infection or blood transfusion reaction.
It can eradicate solid tumors in early stages by only one operation.
It is a local treatment with the minimal effect on the rest of the body and relatively slighter side effects.
Demerits:
It is of little help for hematological cancers (like leukemia) or metastasized ones.
There’s a risk for infection or blood transfusion reaction.
At high doses, radiation therapy kills cancer cells or slows their growth by damaging their DNA. Cancer cells whose DNA is damaged beyond repair stop dividing or die.
Merits:
It has high efficiency and definite curative effects.
It is convenient to be carried out.
It is broad-spectrum and suitable for cancers in most types and most sites of the body.
Demerits:
It kills not only cancer cells but also benign ones on a large scale, and therefore causes damage to nearby tissues and organs.
It can be money-consuming due to high doses of radiation and complex machines involved.
It has a broad range of side effects including fatigue, hair loss, nausea and vomiting and skin changes.
It is even more suffering because the treatment course is always long.
Merits:
It has high efficiency and definite curative effects.
It is convenient to be carried out.
It is broad-spectrum and suitable for cancers in most types and most sites of the body.
Demerits:
It kills not only cancer cells but also benign ones on a large scale, and therefore causes damage to nearby tissues and organs.
It can be money-consuming due to high doses of radiation and complex machines involved.
It has a broad range of side effects including fatigue, hair loss, nausea and vomiting and skin changes.
It is even more suffering because the treatment course is always long.
Chemotherapy can be used to cure cancer, ease the symptoms it causes, lessen the chance it will return, or stop or slow its growth.
Merits:
It can deal with both primary and secondary cancers.
It can help other treatments work better, like making a tumor smaller before surgery or radiation therapy (which is called neoadjuvant chemotherapy) and destroying cancer cells that may remain after treatment with surgery or radiation therapy (which is called adjuvant chemotherapy).
It is broad-spectrum and suitable for cancers in most types and most sites of the body.
It is convenient to be carried out.
Demerits:
The blood–brain barrier poses an obstacle to delivery of chemotherapy to the brain so that chemotherapy is ineffective in some brain tumors.
It is easily to drive resistance.
Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells. Hence, chemotherapy has the potential to harm healthy tissues, especially those tissues that have a high replacement rate (e.g. intestinal lining).
Average cost in China: To reach better therapeutic effects, chemotherapy is often applied with surgery and radiation therapy, the combined cost of which is about 50-150 thousand yuan per year.
Merits:
It can deal with both primary and secondary cancers.
It can help other treatments work better, like making a tumor smaller before surgery or radiation therapy (which is called neoadjuvant chemotherapy) and destroying cancer cells that may remain after treatment with surgery or radiation therapy (which is called adjuvant chemotherapy).
It is broad-spectrum and suitable for cancers in most types and most sites of the body.
It is convenient to be carried out.
Demerits:
The blood–brain barrier poses an obstacle to delivery of chemotherapy to the brain so that chemotherapy is ineffective in some brain tumors.
It is easily to drive resistance.
Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells. Hence, chemotherapy has the potential to harm healthy tissues, especially those tissues that have a high replacement rate (e.g. intestinal lining).
Average cost in China: To reach better therapeutic effects, chemotherapy is often applied with surgery and radiation therapy, the combined cost of which is about 50-150 thousand yuan per year.
Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer. There are two main types of targeted therapies, small-molecule drugs (such as Imatinib mesylate (Gleevec®) and Gefitinib (Iressa®)) and monoclonal antibodies (such as Nivolumab (Opdivo®), Pembrolizumab (Keytruda®) and Trastuzumab (Herceptin®)).
Merits:
Specificity. The way targeted therapy differs from standard chemotherapy most is that it interacts with tumor-associated targets only, causing much less damage to noncancerous cells. Meanwhile, this specificity also contributes to higher efficiency of the cure as a result of the concentration of firepower.
Precision and personalization. Targeted therapies are designed referring to information about a patient’s genes and proteins. They are a cornerstone of precision medicine.
Demerits:
Cancer cells can evolve resistance to target therapies due to mutation and/or invalidation of the target.
Drugs for some identified targets are difficult to develop because of the target’s structure and/or the way its function is regulated in the cell.
Some certain kinds of targeted therapies can have substantial side effects including diarrhea and liver problems, such as hepatitis and elevated liver enzymes.
Taking consideration of time and money costs to design and develop a targeted therapy as well as the advanced technologies involved, this sort of treatment is still expensive at least for now (average cost in China: 200-500 thousand RMB/year).
Merits:
Specificity. The way targeted therapy differs from standard chemotherapy most is that it interacts with tumor-associated targets only, causing much less damage to noncancerous cells. Meanwhile, this specificity also contributes to higher efficiency of the cure as a result of the concentration of firepower.
Precision and personalization. Targeted therapies are designed referring to information about a patient’s genes and proteins. They are a cornerstone of precision medicine.
Demerits:
Cancer cells can evolve resistance to target therapies due to mutation and/or invalidation of the target.
Drugs for some identified targets are difficult to develop because of the target’s structure and/or the way its function is regulated in the cell.
Some certain kinds of targeted therapies can have substantial side effects including diarrhea and liver problems, such as hepatitis and elevated liver enzymes.
Taking consideration of time and money costs to design and develop a targeted therapy as well as the advanced technologies involved, this sort of treatment is still expensive at least for now (average cost in China: 200-500 thousand RMB/year).
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.
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.
Nat Med. 2017 Jun; 23(6): 703–713.
Figure 1 Distribution of the somatic tumor mutation burden (TMB), defined as non-synonymous coding mutations per Megabase (Mb), for common principal tumor types
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”. 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.
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 is then 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”.
Copyright © 2017 Elsevier Inc. Terms and Condition
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, not only because of 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.
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.
References
Bobisse S, Foukas PG, Coukos G, Harari A. Neoantigen-based cancer immunotherapy. Ann Transl Med 2016;4(14):262. doi: 10.21037/atm.2016.06.17
L Li, S P Goedegebuure, W E Gillanders; Preclinical and clinical development of neoantigen vaccines, Annals of Oncology, Volume 28, Issue suppl_12, 1 December 2017, Pages xii11–xii17
NIH>National Cancer Institute
Ott PA , Hu Z, Keskin DB et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 2017; 547(7662): 217–221.
Sahin U , Derhovanessian E, Miller M et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 2017; 547(7662): 222–226.
Treatment for cancer——Wikipedia