Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and How Can These Be Overcome? Neoantigens: Nothing New in Spite of the Name

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Olivera J. Finn1 and Hans-Georg Rammensee2

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 2Department of Immunology, Institute for Cell Biology, University of Tuebingen, 72074 Tuebingen; and German Cancer Consortium, DKFZ Partner Site, D-69120 Heidelberg, Germany Correspondence: [email protected]

The term “neoantigen,” as applied to molecules newly expressed on tumor cells, has a long history. The groundbreaking discovery of a cancer causing virus in chickens by Rous over 100 years ago, followed by discoveries of other tumor-causing viruses in animals, suggested a viral etiology of human cancers. The search for other oncogenic viruses in the 1960s and 1970s resulted in the discoveries of Epstein–Barr virus (EBV), hepatitis B virus (HBV), and human papilloma virus (HPV), and continues until the present time. Contemporaneously, the budding field of immunology was posing the question can the immune system of animals or humans recognize a tumor that develops from one’s own tissues and what types of antigens would distinguish the tumor from normal cells. Molecules encoded by oncogenic viruses provided the most logical candidates and evidence was quickly gathered for both humoral and cellular recognition of viral antigens, referred to as neoantigens. Often, however, serologic responses to virus-bearing tumors revealed neoantigens unrelated toviral proteins and expressed on multiple tumor types, foreshadowing later findings of multiple changes in other genes in tumor cells creating nonviral neoantigens.

GREAT DEBATES

What are the most interesting topics likely to come up over dinner or drinks with your colleagues? Or, more importantly, what are the topics that don’t come up because they are a little too controversial? In Immune Memory and Vaccines: Great Debates, Editors Rafi Ahmed and Shane Crotty have put together a collection of articles on such questions, written by thought leaders in these fields, with the freedom to talk about the issues as they see fit. This short, innovative format aims to bring a fresh perspective by encouraging authors to be opinionated, focus on what is most interesting and current, and avoid restating introductory material covered in many other reviews. The Editors posed 13 interesting questions critical for our understanding of vaccines and immune memory to a broad group of experts in the field. In each case, several different perspectives are provided. Note that while each author knew that there were additional scientists addressing the same question, they did not know who these authors were, which ensured the independence of the opinions and perspectives expressed in each article. Our hope is that readers enjoy these articles and that they trigger many more conversations on these important topics.

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O.J. Finn and H.-G. Rammensee

Use the right word, not its second cousin. last two decades, many TAAs have been iden- — Mark Twain tified and the nature of tumor-specific changes Groundbreaking discoveries in the early 1970s, in normal cellular proteins that created these starting with the identification of the src onco- neoantigens was elucidated. Shared neoanti- gene, showed that cancer was a genetic disease gens belong to one of several categories: onco- and that abnormal expression (activation or fetal antigens (expressed in fetal but not adult suppression) of proto-oncogenes could cause tissues and reexpressed in tumors), cancer/tes- malignant transformation. Products of mutated tis (CT) antigens (present in germ cells that proto-oncogenes became candidate tumor lack major histocompatibility complex [MHC] neoantigens (Hellstrom and Hellstrom 1989; and not presented to the immune system except Urban and Schreiber 1992). Simultaneous de- on tumor cells), differentiation antigens (specif- velopment of molecular techniques and cellular ic to differentiated tissues and organs from assays to evaluate T-cell responses in vitro which the tumor originated), overexpressed identified numerous mutated neoantigens, antigens and differentially processed antigens products of single-point mutations in genes en- (tumor-specific changes in protein glycosyla- coding proteins directing various cellular function [Vlad and Finn 2004; Vankemmelbeke et tions newly expressed and unique to each in- al. 2016], phosphorylation [Mohammed et al. dividual mouse and human tumor (Sibille et al. 2008], and citrullination [Brentville et al. 1990; Lennerz et al. 2005; Sensi and Anichini 2016]), among others. 2006; Coulie et al. 2014). These data recapitu- In summary, over a period of more than half lated results from early work on mouse carcin- a century, a long list of neoantigens has been ogen-induced tumors that identified unique compiled, which regardless of their origin (viral, mutations generating neoantigens that elicited mutated, nonmutated) share the same charac- immunity and protected mice from challenge teristics: (1) they are newly and preferentially with the original tumor but no other tumors present on tumor cells; (2) recognized by anti- caused by the same carcinogen (Srivastava bodies and T cells; and (3) elicit spontaneous 2015). immunity in cancer patients and tumor-rejec- All of these neoantigens (viral, oncogene- tion immunity in animal models. It is thus un- encoded, or randomly mutated) were the pre- justified that the term “neoantigens” has recent- dicted targets of cancer immunosurveillance, a ly been usurped specifically for products of function of the immune system that was at that mutated gene segments uncovered by whole time very much in doubt and for which their exome sequencing or by mass spectrometric identification provided an indisputable support analysis of MHC/human leukocyte antigen (Dunn et al. 2004). What was not predicted (HLA)-bound peptides (Bassani-Sternberg et when the search for tumor antigens began al. 2015; Kalaora et al. 2016). This misuse of was the finding of tumor-specific humoral terminology hides the nature and immunogenic and cellular immune responses in mice and in potential of other neoantigens mentioned cancer patients, which recognized nonmutated above, which have already been shown to be cellular proteins as specific antigens on tumor recognized by the immune system, to induce cells and not on normal cells (Sjogren 1967; tumor-rejection immunity in animal models, Finn 1993; Henderson and Finn 1996). Because and to have clinical benefit in cancer patients these were present on multiple tumors rather either as targets of immunotherapy or as vaccine than being unique to each tumor, they were antigens (Cheever et al. 2009). To use the right given a designation “shared tumor antigens” word and not its second cousin, which is espe- (Ting and Herberman 1974). Because they cially important in science communication, were tumor-associated versions of proteins ex- what are recently being referred to as “neoanti- pressed by normal cells and thus not theoreti- gens” should be referred to as “mutated neoan- cally “tumor-specific,” they were also named tigens” in deference to other members of a large tumor-associated antigens (TAAs). Over the and varied family of tumor neoantigens.

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Is It Possible to Develop Cancer Vaccines to Neoantigens?

CANCER VACCINES BASED ON MUTATED sections of primary tumors and metastatic sites, NEOANTIGENS CAN BE DEVELOPED BUT the same cannot be assumed for mutated neo- DO NOT WARRANT SPECIAL ATTENTION antigens. Furthermore, many nonmutated neoantigens trigger immune responses because of Because it is now relatively easy to sequence their overexpression in tumors compared to genes, a cottage industry has sprung up around normal cells. Protein abundance and protein identifying and cataloging hundreds to thou- turnover are important factors for HLA pre- sands of mutations in cancers, each potentially sentation of antigens (Bassani-Sternberg et al. a candidate neoantigen for an individual tumor/ 2015). Identification of mutated peptides as individual patient-specific vaccine, or a target potential neoantigens currently requires a com- for immunotherapy (Boegel et al. 2014; Yadav bination of exome sequencing, messenger RNA et al. 2014). Those who are in the field of tumor (mRNA) microarrays, and epitope predic- immunology trying to better understand tumor tion algorithms, but also knowing the level of immunity and immunosurveillance appreciate expression of the source protein, which deter- the challenges brought about by tumor-specific/ mines whether it can reach the threshold re- patient-specific mutated epitopes (Lutz and Jaf- quired for its efficient processing and presenta- fee 2014; Gubin et al. 2015) and their use for tion in HLA. immunotherapy or vaccines. The major challenges include (1) how to select from a large MUTATED VERSUS NONMUTATED TUMOR number of mutations those few that are made PEPTIDES AS HLA LIGANDS into proteins and processed and presented as antigenic peptides in MHC class I or class II Rammensee and colleagues have characterized antigens; (2) how to show convincingly that im- immunopeptidomes of a number of primary tu- mune responses against mutated neoantigens mors and cells, including leukemias and solid are superior to nonmutated neoantigens; (3) tumors (Walz et al. 2015; Löffler et al. 2016), how to deal with MHC/HLA restriction and by eluting and sequencing peptides from puri- further mutations that can generate antigen-es- fied HLA class I and class II molecules (Berlin cape variants; and (4) how to obtain evidence, et al. 2015). With the current sensitivity of the other than through single-cell sequencing, that mass spectrometry methods, 5000 unique non- specific mutations are present in all tumor cells, mutated peptides can be isolated from 1 g of thus not allowing immune escape (Verdegaal tissue. Hundreds of nonmutated peptides iden- et al. 2016). tified from each sample appear to be tumor spe- Some of these challenges are the same for cific on the grounds that they are not found on viral and nonmutated neoantigen vaccines but any of the numerous normal tissues similarly others are not. For example, every tumor cell in analyzed. Many of these peptides are immuno- a virally induced tumor expresses viral neoanti- genic, as tested by in vitro priming of T cells gens required for continued oncogenic transfor- from healthy donors or by measuring recall T- mation and thus each tumor cell is a target of a cell responses from patients. In chronic lym- vaccine based on these neoantigens (McAllister phocytic leukemia (CLL) patients, such T-cell 1965; Javier and Butel 2008). Similarly, many responses correlated with patients’ overall sur- nonmutated neoantigens, but especially those vival (Kowalewski et al. 2015a). that have oncogenic functions (Cheever et al. By combining exome sequencing, predic- 1995; Bright et al. 2014), such as Her-2neu (Disis tion of mutated peptides as HLA ligands, and et al. 1994), MUC1 (Cheever et al. 1995), hTERT their verification by mass spectrometry, a few (Vonderheide 2002), and p53 (Pedersen et al. mutated peptides were also identified; however, 2011), are expressed in all tumor cells and on only a very small fraction of mutations at the multiple tumor types, which makes them opti- DNA sequence level ended up as peptides in mal candidates for vaccines and immunothera- HLA class I. Based on their own mass spectrom- py. Short of sequencing single cells from various etry data and the published data on the expres-

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O.J. Finn and H.-G. Rammensee

sion of mutations in proteins and HLA ligands, their processing and consequently a difference Rammensee and colleagues (Löffler et al. 2016) in the tumor immunopeptidome. For example, a estimate that from 1000 nonsynonymous DNA mutation in a member of the WNT-signaling mutations, 10 manifest in mutated proteins and pathway (MacDonald et al. 2009) increases lev- only one as a mutated HLA class I ligand (for els of cyclin D1, which in turn increases the illustration, see Fig. 1). Assuming also that the number of its HLA ligands and leads to their tumor proteome is cross-presented on HLA recognition as tumor-specific, nonmutated neo- class II molecules on tumor-associated anti- antigens. Peptides from nonmutated cyclin D1 gen-presenting cells, the frequency of mutated have been shown to be immunogenic and are HLA class II ligands is estimated to be close to already being tested in cancer immunotherapy the number of mutated proteins, 10/1000. These (Walter et al. 2012; Löffler et al. 2016). Another numbers are roughly in accordance with clinical example is cyclin B1, a shared nonmutated tu- observations on mutation-specific T cells from mor antigen that is overexpressed in human patients treated with checkpoint blockade tumors where p53 is either deleted or mutated (Schumacher and Schreiber 2015). (Kao et al. 2001; Yu et al. 2002). The nonmu- In contrast, the number of nonmutated but tated but overexpressed cyclin B1 serves as a still highly tumor-specific peptides is much tumor-rejection antigen in mouse models (Vella higher with several dozens of such peptides et al. 2009) and elicits antibodies and T cells in identified in a given tumor tissue, most of cancer patients (Suzuki et al. 2005). Mutation- them present in one particular tumor and not induced alterations can affect mRNA expression in most other tumors or normal tissues. One levels, RNA splicing, and other posttranscrip- hypothesis is that a mutation anywhere in a pro- tional or posttranslational modifications, re- tein would lead to changes in its expression and sulting in many tumor-specific MHC ligands likely expression of downstream proteins in the as nonmutated neoantigens (Kowalewski et al. same functional pathway, thereby influencing 2015a,b).

Cancer cell

1000 Mutations at DNA sequence level

10 Protein

MHC I 1 HLA class I ligandome

APC MHC II x? Cross-presented HLA class II ligandome

Figure 1. Frequency of mutated neoantigens presented in major histocompatibility complex (MHC) class I and cross-presented in MHC class II. APC, Antigen-presenting cell; HLA, human leukocyte antigen.

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Is It Possible to Develop Cancer Vaccines to Neoantigens?

IMPORTANCE OF CHOOSING THE RIGHT NEOANTIGENS AS PROPHYLACTIC CANCER NEOANTIGEN(S) FOR EFFECTIVE CANCER VACCINES? VACCINES In addition to combination therapies designed A recent explosion in the number of mutated to enhance efficacy of therapeutic cancer vac- neoantigens and the enthusiasm for their po- cines, some cancer vaccines are already being tential as cancer vaccines should not distract tested for increased efficacy in individuals with- from the fact that mutated neoantigen vaccines out cancer but at an increased risk for cancer. are not a new concept and have been made The hypothesis is that in the absence of tumor and tested before. This includes vaccines based the immune system is not compromised and on mutated H-ras (Gjertsen and Gaudernack effective immunity and immune memory can 1998) and K-ras oncogenes (Carbone et al. be elicited to protect from or delay tumor devel- 2005), mutated p53 (Carbone et al. 2005; Ver- opment (Finn 2014). Initial trials are based on meij et al. 2011), and heat-shock proteins that several well-known shared tumor antigens that bind mutated tumor peptides (Srivastava 1993). have been extensively studied and thoroughly These vaccines have had as much or as little characterized for their expression on tumors success as vaccines based on nonmutated over- (Finn and Beatty 2016). One of these is MUC1 expressed antigens, CT antigens, or differentia- that is overexpressed in its hypoglycosylated tion antigens. The rationale for their develop- form on all human adenocarcinomas as well as ment as vaccines was that they were tumor- on multiple myeloma and some leukemias and specific and foreign to the immune system lymphomas. The expectation is that the MUC1 and should induce stronger immune responses vaccine would elicit or boost strong immune than nonmutated neoantigens that might be responses and long-term immune memory to subject to immune tolerance. This predicted prevent cancer development. Finn and col- difference between mutated and nonmutated leagues are vaccinating individuals diagnosed neoantigens did not materialize, nor did the with advanced adenomas of the colon, precur- immunogenic superiority of mutated antigens. sors to colon cancer. The vaccine is given post- A good example is p53 where vaccines based on adenoma removal and a booster is administered patient- and tumor-specific p53-mutated neo- a year later. Very strong anti-MUC1 immune epitopes achieved the same results as vaccines responses were induced in the initial study that based on nonmutated peptides derived from greatly surpassed frequency and intensity of re- overexpressed wild-type p53 (Vermeij et al. sponses seen in cancer patients. Importantly, the 2011). It is clear now that the immunosuppres- vaccine induced immune memory with no evi- sive tumor microenvironment (Palucka and dence of toxicity (Kimura et al. 2013). Vaccine- Coussens 2016) can have a much greater effect elicited antibodies had a range of affinities and on vaccine immunogenicity and efficacy than reacted only with MUC1 on tumors and not on the nature of the vaccine antigen. Given past normal tissues (Lohmueller et al. 2016). Inas- experience with mutated neoantigens, it is much as the nonmalignant adenomas also over- hard to justify the labor- and cost-intensive de- express hypoglycosylated MUC1, this vaccine is velopment of personalized vaccines based on expected to prevent recurrence of premalignant these antigens. It is more than likely that to be lesions or their progression to cancer. This is more effective in the therapeutic setting, all can- being tested in an ongoing randomized trial. cer vaccines will need help from currently avail- The absence of cancer as a source of mutated able or soon-to-be-developed immunotherapies neoantigens would appear to exclude the possi- directed at modulating the tumor microenvi- bility of developing personalized prophylactic ronment (Kourie et al. 2016). If these immuno- cancer vaccines. Whereas this is the case in the modulators are successful, both nonmutated true prevention setting in the complete absence and mutated neoepitope vaccines will experi- of disease, it does not apply to the setting of ence a renaissance. premalignant disease (Finn 2003). Most human

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Is It Possible to Develop Cancer Vaccines to Neoantigens?

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O.J. Finn and H.-G. Rammensee

nogenicity of somatic mutations in human gastrointesti- Vonderheide RH. 2002. Telomerase as a universal tumor- nal cancers. Science 350: 1387–1390. associated antigen for cancer immunotherapy. Oncogene 21: – Urban JL, Schreiber H. 1992. Tumor antigens. Annu Rev 674 679. Immunol 10: 617–644. Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Vankemmelbeke M, Chua JX, Durrant LG. 2016. Cancer cell Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendr- associated glycans as targets for immunotherapy. On- zyk R, et al. 2012. Multipeptide immune response to can- coimmunology 5: e1061177. cer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18: 1254– Vella LA, Yu M, Phillips AB, Finn OJ. 2009. Immunity 1261. against cyclin B1 tumor antigen delays development of –/– Walz S, Stickel JS, Kowalewski DJ, Schuster H, Weisel K, spontaneous cyclin B1-positive tumors in p53 mice. Backert L, Kahn S, Nelde A, Stroh T, Handel M, et al. Ann NY Acad Sci 1174: 68–73. 2015. The antigenic landscape of multiple myeloma: Verdegaal EM, de Miranda NF, Visser M, Harryvan T, van Mass spectrometry (re)deﬁnes targets for T-cell-based Buuren MM, Andersen RS, Hadrup SR, van der Minne immunotherapy. Blood 126: 1203–1213. CE, Schotte R, Spits H, et al. 2016. Neoantigen landscape Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay dynamics during human melanoma–T cell interactions. 536: – J, Bumbaca S, Franci C, Cheung TK, Fritsche J, Wein- Nature 91 95. schenk T, et al. 2014. Predicting immunogenic tumour Vermeij R, Leffers N, van der Burg SH, Melief CJ, Daemen T, mutations by combining mass spectrometry and exome Nijman HW. 2011. Immunological and clinical effects of sequencing. Nature 515: 572–576. vaccines targeting p53-overexpressing malignancies. J Bi- Yu M, Zhan Q, Finn OJ. 2002. Immune recognition of cyclin 2011: omed Biotechnol 702146. B1 as a tumor antigen is a result of its overexpression in Vlad AM, Finn OJ. 2004. Glycoprotein tumor antigens for human tumors that is caused by non-functional p53. Mol immunotherapy of breast cancer. Breast Dis 20: 73–79. Immunol 38: 981–987.

8 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a028829 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press

Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and How Can These Be Overcome?: Neoantigens: Nothing New in Spite of the Name

Olivera J. Finn and Hans-Georg Rammensee

Cold Spring Harb Perspect Biol published online December 18, 2017

Subject Collection Immune Memory and Vaccines: Great Debates

Is There Natural Killer Cell Memory and Can It Be Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination?: Can Natural Killer Harnessed by Vaccination?: NK Cell Memory and and CD8 T Cells Switch Jobs? Immunization Strategies against Infectious Christine A. Biron and Marcus Altfeld Diseases and Cancer Joseph C. Sun and Lewis L. Lanier Is There Natural Killer Cell Memory and Can It Be Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination?: Vaccination Harnessed by Vaccination?: Natural Killer Cells in Strategies Based on NK Cell and ILC Memory Vaccination Megan A. Cooper, Todd A. Fehniger and Marco Harold R. Neely, Irina B. Mazo, Carmen Gerlach, et Colonna al. Is It Possible to Develop Cancer Vaccines to Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and Neoantigens, What Are the Major Challenges, and How Can These Be Overcome?: Neoantigens as How Can These Be Overcome?: Targeting the Vaccine Targets for Cancer Right Antigens in the Right Patients Haydn T. Kissick Stephen P. Schoenberger Is It Possible to Develop Cancer Vaccines to Which Dengue Vaccine Approach Is the Most Neoantigens, What Are the Major Challenges, and Promising, and Should We Be Concerned about How Can These Be Overcome?: Neoantigens: Enhanced Disease after Vaccination?: There Is Nothing New in Spite of the Name Only One True Winner Olivera J. Finn and Hans-Georg Rammensee Scott B. Halstead Which Dengue Vaccine Approach Is the Most Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Promising, and Should We Be Concerned about Enhanced Disease after Vaccination?: The Enhanced Disease after Vaccination?: Questions Challenges of a Dengue Vaccine Raised by the Development and Implementation Gavin Screaton and Juthathip Mongkolsapaya of Dengue Vaccines: Example of the Sanofi Pasteur Tetravalent Dengue Vaccine Bruno Guy

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Which Dengue Vaccine Approach Is the Most Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Promising, and Should We Be Concerned about Enhanced Disease after Vaccination?: The Path to Enhanced Disease after Vaccination?: The Risks a Dengue Vaccine: Learning from Human Natural of Incomplete Immunity to Dengue Virus Revealed Dengue Infection Studies and Vaccine Trials by Vaccination Aravinda M. de Silva and Eva Harris Stephen S. Whitehead and Kanta Subbarao Is It Possible to Develop a ''Universal'' Influenza Is It Possible to Develop a ''Universal'' Influenza Virus Vaccine?: Potential for a Universal Influenza Virus Vaccine?: Immunogenetic Considerations Vaccine Underlying B-Cell Biology in the Development of a James E. Crowe, Jr. Pan-Subtype Influenza A Vaccine Targeting the Hemagglutinin Stem Sarah F. Andrews, Barney S. Graham, John R. Mascola, et al. Is It Possible to Develop a ''Universal'' Influenza Is It Possible to Develop a ''Universal'' Influenza Virus Vaccine?: Outflanking Antibody Virus Vaccine?: Potential Target Antigens and Immunodominance on the Road to Universal Critical Aspects for a Universal Influenza Vaccine Influenza Vaccination Florian Krammer, Adolfo García-Sastre and Peter Davide Angeletti and Jonathan W. Yewdell Palese

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