Targeting public neoantigens for cancer immunotherapy

Alexander H Pearlman^{1

2

3}, Michael S Hwang^{1

2

3

4}, Maximilian F Konig^{1

2

3

5}, Emily Han-Chung Hsiue^{1

2

3}, Jacqueline Douglass^{1

2

3}, Sarah R DiNapoli^{1

2

3}, Brian J Mog^{1

2

3

6}, Chetan Bettegowda^{1

2

7

8}, Drew M Pardoll^{8

9}, Sandra B Gabelli^{8

10

11}, Nicholas Papadopoulos^{1

2

9

12

13}, Kenneth W Kinzler^{1

2

8

9

13}, Bert Vogelstein^{1

2

3

8

9

12

13}, Shibin Zhou^{14

15

16

17}

Affiliations

¹ Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁴ Genentech, Inc., South San Francisco, CA, USA.
⁵ Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁷ Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
¹⁰ Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. sbzhou@jhmi.edu.
¹⁵ Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. sbzhou@jhmi.edu.
¹⁶ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. sbzhou@jhmi.edu.
¹⁷ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. sbzhou@jhmi.edu.

PMID: 34676374
PMCID: PMC8525885
DOI: 10.1038/s43018-021-00210-y

Review

Targeting public neoantigens for cancer immunotherapy

Alexander H Pearlman et al. Nat Cancer. 2021 May.

. 2021 May;2(5):487-497.

doi: 10.1038/s43018-021-00210-y. Epub 2021 May 17.

Authors

Affiliations

¹ Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁴ Genentech, Inc., South San Francisco, CA, USA.
⁵ Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁷ Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
¹⁰ Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. sbzhou@jhmi.edu.
¹⁵ Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. sbzhou@jhmi.edu.
¹⁶ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. sbzhou@jhmi.edu.
¹⁷ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. sbzhou@jhmi.edu.

PMID: 34676374
PMCID: PMC8525885
DOI: 10.1038/s43018-021-00210-y

Erratum in

Author Correction: Targeting public neoantigens for cancer immunotherapy.
Pearlman AH, Hwang MS, Konig MF, Hsiue EH, Douglass J, DiNapoli SR, Mog BJ, Bettegowda C, Pardoll DM, Gabelli SB, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S. Pearlman AH, et al. Nat Cancer. 2021 Aug;2(8):865-867. doi: 10.1038/s43018-021-00246-0. Nat Cancer. 2021. PMID: 35122030 Free PMC article. No abstract available.

Abstract

Several current immunotherapy approaches target private neoantigens derived from mutations that are unique to individual patients' tumors. However, immunotherapeutic agents can also be developed against public neoantigens derived from recurrent mutations in cancer driver genes. The latter approaches target proteins that are indispensable for tumor growth, and each therapeutic agent can be applied to numerous patients. Here we review the opportunities and challenges involved in the identification of suitable public neoantigen targets and the development of therapeutic agents targeting them.

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Conflict of interest statement

Competing interests The Johns Hopkins University has filed patent applications related to technologies described in this paper, on which A.H.P., M.S.H., E.H.-C.H., J.D., B.J.M., N.P., K.W.K., B.V., D.M.P. and S.Z. are listed as inventors: HLA-restricted epitopes encoded by somatically mutated genes (15/560,241, USPTO; 2016235251, European Patent Office); MANAbodies and Methods of Using (16/614,005, USPTO; 18802867.4, European Patent Office); MANAbodies Targeting Tumor Antigens and Methods of Using (63/059,638, USPTO; PCT/US2020/065617, World IP Organization). These applications include methods for identifying public neoantigens and the development of therapeutic agents that target these neoantigens. B.V., K.W.K. and N.P. are founders of Thrive Earlier Detection. K.W.K. and N.P. are consultants to Thrive Earlier Detection and were on its Board of Directors. B.V., K.W.K., N.P. and S.Z. own equity in Exact Sciences. B.V., K.W.K., N.P., S.Z. and D.M.P. are founders of, and serve or may serve as consultants to, ManaT Bio, and hold or may hold equity in ManaT Holdings, LLC. B.V., K.W.K., N.P. and S.Z. are founders of, hold equity in and serve as consultants to Personal Genome Diagnostics. S.Z. has a research agreement with BioMed Valley Discoveries. S.B.G. is a founder of and holds equity in AMS. K.W.K. and B.V. are consultants to Sysmex, Eisai and Cage Pharma and hold equity in Cage Pharma. B.V. is also a consultant to Catalio. K.W.K., B.V., S.Z. and N.P. are consultants to and hold equity in NeoPhore. N.P. is an advisor to and holds equity in Cage Pharma. C.B. is a consultant to DePuy Synthes and Bionaut Labs. The companies named above, as well as other companies, have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. B.V., K.W.K., S.Z., N.P. and C.B. are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors, as well as to Johns Hopkins University. The terms of all of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. M.F.K. received personal fees from Bristol Myers Squibb and Celltrion. D.M.P. reports grant and patent royalties through his institution from Bristol Myers Squibb, a grant from Compugen, stock from Trieza Therapeutics and Dracen Pharmaceuticals and founder equity from Potenza; is a consultant for Aduro Biotech, Amgen, AstraZeneca (MedImmune/Amplimmune), Bayer, DNAtrix, Dynavax Technologies Corporation, Ervaxx, FLX Bio, Rock Springs Capital, Janssen, Merck, Tizona and Immunomic Therapeutics; is on the scientific advisory board of Five Prime Therapeutics, Catalio and WindMIL; and is on the board of directors for Dracen Pharmaceuticals.

Figures

**Fig. 1 |. Generation and immune recognition of public neoantigens.**
a, Amino acid alterations can enable a mutant peptide to be processed differently for presentation or to bind to the HLA, whereas the wild-type peptide does not bind. b, Differential contact with the TCR by a mutant amino acid residue allows discrimination between the mutant and wild-type peptides within the HLA. c, The overall structure of the peptide–HLA–TCR binding interface is altered through altered conformation of mutant peptide binding, distinguishing the mutant peptide from the wild-type peptide. d, Genetic mutations produce changes in the amino acid sequences of proteins. These proteins with altered sequences can be degraded by the proteasome and the resulting peptides can be processed and presented by HLA on the cell surface. The genes listed are those for which public neoantigens have been identified with defined HLA restriction and strong evidence for endogenous presentation (Supplementary Table 1).

**Fig. 2 |. Strategies to target public neoantigens.**
Sequencing of tumor specimens from patients enables mutation identification and HLA typing. Patients can then be matched to appropriate therapies for targeting their identified public neoantigens. These therapies include vaccines, TCR-T cells, CAR-T cells and bispecific antibodies.

**Fig. 3 |. Frequency of recurrent mutations across cancer types.**
For the top 12 solid tumor organ sites projected to be responsible for most new cancer cases in the United States in 2020 (National Cancer Institute Surveillance, Epidemiology, and End Results Cancer Statistics Factsheets; https://seer.cancer.gov/statfacts/html/common.html), the corresponding The Cancer Genome Atlas (TCGA) projects were selected. Shown are the frequencies of occurrence in each TCGA project of each substitution that accounts for at least 5% of cases in at least one TCGA project. Sum represents the summation of frequencies of all included mutations for a given TCGA project.

See this image and copyright information in PMC

References

1. Schumacher TN, Scheper W & Kvistborg P Cancer neoantigens. Annu. Rev. Immunol 37, 173–200 (2019). - PubMed
1. Vogelstein B et al. Cancer genome landscapes. Science 339, 1546–1558 (2013). - PMC - PubMed
1. Leko V & Rosenberg SA Identifying and targeting human tumor antigens for T cell-based immunotherapy of solid tumors. Cancer Cell 38, 454–472 (2020). - PMC - PubMed
1. Deniger DC et al. T-cell responses to TP53 ‘hotspot’ mutations and unique neoantigens expressed by human ovarian cancers. Clin. Cancer Res 24, 5562–5573 (2018). - PMC - PubMed
1. Parkhurst MR et al. Unique neoantigens arise from somatic mutations in patients with gastrointestinal cancers. Cancer Discov. 9, 1022–1035 (2019). - PMC - PubMed

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Targeting public neoantigens for cancer immunotherapy

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Targeting public neoantigens for cancer immunotherapy

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