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(51) International Patent Classification: A61K 39/00 (2006.01) G01N 33/68

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(51) International Patent Classification: A61K 39/00 (2006.01) G01N 33/68 ( (51) International Patent Classification: Published: A61K 39/00 (2006.01) G01N 33/68 (2006.01) — with international search report (Art. 21(3)) G01N 33/574 (2006.01) — before the expiration of the time limit for amending the (21) International Application Number: claims and to be republished in the event of receipt of PCT/EP2020/06 1841 amendments (Rule 48.2(h)) — with sequence listing part of description (Rule 5.2(a)) (22) International Filing Date: 29 April 2020 (29.04.2020) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 19171495.5 29 April 2019 (29.04.2019) EP (71) Applicant: VACCIBODY AS [NO/NO]; Gaustadalleen 21, 0349 Oslo (NO). (72) Inventors: FREDRIKSEN, Agnete, Brunsvik; 0vre Raslingsveg 82b, 2005 Raslingen (NO). SEKELJA, Moni¬ ka; Jarisborgveien li, 0379 Oslo (NO). SCHJETNE, Karoline; Johnsrudgata 48, 1350 Lonunedalen (NO). (74) Agent: H0IBERGP/S; Adelgade 12, 1304 CopenhagenK (DK). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — of inventorship (Rule 4.17 (iv)) (54) Title: METHODS FOR PRE-SELECTION OF NEOEPITOPES (57) Abstract: The present invention relates to methods for pre-selecting neoepitopes likely to have clinical utility, methods for prepar¬ ing cancer vaccines comprising the pre-selected neoepitopes and methods for preparing T-cells having the ability to specifically recog¬ nise a neoepitope in an individual. Also provided are cancer vaccines comprising the pre-selected neoepitopes, T-cells obtainable by the present methods and compositions comprising such T-cells, as well as their use for treating or preventing cancer, and methods for inducing or increasing an immune response in an individual. Methods for pre-selection of neoepitopes Technical field The present invention relates to methods for pre-selecting neoepitopes likely to have clinical utility, methods for preparing cancer vaccines comprising the pre-selected neoepitopes, and methods for preparing T-cells having the ability to specifically recognise a neoepitope in an individual. Also provided are cancer vaccines comprising the pre-selected neoepitopes, T-cells obtainable by the present methods and compositions comprising such T-cells, as well as their use for treating or preventing cancer, and methods for inducing or increasing an immune response in an individual. Background Although treatment of cancer has been improved over the past few decades in particular due to early detection and diagnosis, which has significantly increased the survival, only about 60% of patients diagnosed with cancer are alive 5 years after the diagnosis. Most of the cancer treatments in use are surgical procedures, radiation and cytotoxic chemotherapeutics. However they all have serious side effects. Recently also treatment using antibodies directed towards known cancer associated antigens or immunomodulatory molecules have been used. Within the last few years cancer immune therapies targeting cancer cells with the help of the patient's own immune system, e.g. cancer vaccines, have attracted interest because such therapies may reduce or even eliminate some of the side-effects seen in the traditional cancer treatment. The foundation of immunology is based on discrimination between self and non-self. Most of the pathogens inducing infectious diseases contain molecular signatures that can be recognized by the host and trigger immune responses. However tumor cells are derived from normal cells, and do not generally express any foreign molecular signatures, making them more difficult to be distinguished from normal cells. Nevertheless, most tumor cells express different types of tumor antigens. One class of tumor antigens are the so-called tumor associated antigens, e.g. antigens expressed at low levels in normal tissues and expressed at a much higher level in tumor tissue. Such tumor associated antigens have been the target for cancer vaccines for the last decade. However, immunological treatment directed towards tumor associated antigens exhibit several challenges, in that the tumor cells may evade the immune system by downregulating the antigen in question, and the treatment may also lead to toxicities due to normal cell destruction. Recently, another class of tumor antigens have been identified, the so-called tumor neoantigens which are tumor specific-antigens. Tumor neoantigens arise due to one or more mutations in the tumor genome leading to a change in the amino acid sequence of the protein in question. Since these mutations are not present in normal tissue, the side-effects of the treatment directed towards the tumor-specific neoantigens do not arise with an immunologic treatment towards tumor neoantigens. However, to create efficient vaccines it is important that the most clinically relevant neoepitopes are selected and used for the vaccine. Summary The invention is as defined in the claims. The inventors of the present invention have developed a neoepitope selection process to select neoepitopes that have properties proven to be important for immunogenicity, and which are most likely to be useful to induce the desired immune response in an individual. By using the present methods, useful neoepitopes such as highly immunogenic neoepitopes predicted to bind the major histocompatibility complex (MHC) can be selected for vaccines thereby resulting in vaccines capable of inducing a strong and robust immune-response. In particular, the vaccines can be used for neoepitope-based cancer treatment. The neoepitopes are selected from neoepitopes which are ranked according to a number of parameters. For example, neoepitopes which can induce a strong immune response when administered in a cancer vaccine but which prior to vaccine administration induce a weak or no immune response in the individual prior to administration of a vaccine are prioritized as they are expected to have higher clinical utility or relevance than neoepitopes which can induce a strong immune response when administered in a cancer vaccine but which already induce a strong immune response prior to vaccine administration. In other words, neoepitopes inducing a weak or no baseline immune response are considered most likely to be clinically relevant, particularly for the purpose of manufacturing neoepitope-based vaccines as described herein. Vaccines suitable for personalised cancer therapy may thus be generated. Herein are thus provided methods for ranking neoepitopes according to their clinical utility, which are particularly suitable in the context of producing personalised vaccines for cancer therapy. Herein is thus provided a method for selecting a number A of neoepitopes for an individual, comprising the steps of: i) Obtaining one or more neoepitopes from said individual, each neoepitope comprising at least one minimal epitope, wherein each neoepitope comprises at least one mutation such as an immunogenic mutation compared to a reference sequence, wherein the minimal epitope comprises said mutation; ii) Determining a baseline immune response to each of said one or more neoepitopes in said individual; iii) Ranking said one or more neoepitopes with respect to the strength of the baseline immune responses determined in step ii); iv) Selecting the neoepitopes inducing weak baseline immune responses; wherein optionally the immune response is a lymphocyte response such as a T-cell response, wherein preferably the individual has not been administered a neoepitope-based cancer therapy at any point before step i), ii), iii) or iv), thereby selecting A neoepitopes likely to have clinical utility. Alternatively herein is thus provided a method for selecting a number A of neoepitopes for an individual, comprising the steps of: i) Determining a baseline immune response to one or more neoepitopes from said individual, each neoepitope comprising at least one minimal epitope, wherein each neoepitope comprises at least one mutation, wherein the minimal epitope comprises said mutation; ii) Ranking said one or more neoepitopes with respect to the strength of the baseline immune responses determined in step i); and iii) Selecting a number A of neoepitopes inducing weak baseline immune responses. In one embodiment, the at least one mutation is an immunogenic mutation. In another embodiment, the immune response is a lymphocyte response such as a T-cell response. In a preferred embodiment, the individual has not been administered a neoepitope-based cancer therapy at any point before step i), ii) or iii). By the aforementioned method, a number A of neoepitopes are selected that are likely to have clinical utility. Also provided is a method for preparing a cancer vaccine comprising A neoepitopes, said method comprising a step of selecting said neoepitopes using the methods described herein. Also provided is a cancer vaccine for use in a method of treating or preventing a cancer in an individual in need thereof, wherein said cancer vaccine is as defined in any one of the preceding claims, the method comprising the step of administering the cancer vaccine to the individual in need thereof, optionally in combination with another cancer treatment such as administration of a checkpoint inhibitor.
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