Methods and materials for evaluating and treating cancer

Abstract

This document relates to methods and materials relating to the evaluation of mammals (e.g., humans) with cancer (e.g., metastatic cancer), the preparation of treatment for mammals (e.g., humans) with cancer (e.g., metastatic cancer), and / or treatment for mammals (e.g., humans) with cancer (e.g., metastatic cancer). For example, it provides methods and materials for identifying cancers (e.g., metastatic cancers) that are likely to respond to adoptive cell therapy (e.g., tumor-infiltrating lymphocyte therapy).

Description

[Technical Field]

[0001] References to related applications This application claims priority to U.S. Patent Application No. 63 / 466,530, filed on 15 May 2023. The disclosures of the prior application are deemed to be part of the disclosures of this application and are incorporated by reference thereto.

[0002] This specification relates to methods and materials relating to the evaluation and / or treatment of mammals (e.g., humans) having cancer (e.g., metastatic cancer). For example, the methods and materials provided herein can be used to identify cancers (e.g., metastatic cancers) that are likely to respond to adoptive cell therapy (ACT; e.g., tumor-infiltrating lymphocyte (TIL) therapy). As another example, the methods and materials provided herein can be used to treat mammals (e.g., humans) having cancer (e.g., metastatic cancer). As yet another example, the methods and materials provided herein can be used to treat mammals (e.g., humans) having cancer (e.g., metastatic cancer), and the cancer treatment is selected based on whether the cancer is likely to respond to ACT (e.g., TIL therapy). [Background technology]

[0003] ACT has improved cancer outcomes in many patients. For example, TIL therapy can mediate the regression of metastatic tumors in several solid tumor types that are resistant to other cancer treatments, such as immune checkpoint inhibitors. However, to determine eligibility for TIL therapy, patients must undergo surgical collection of tumor samples and then wait approximately three weeks for the samples to be tested for TIL growth and TIL tumor reactivity. This tumor sample testing process is time-consuming and resource-intensive (see, for example, Rosenberg et al., Science, 348(6230):62-8 (2015); and Chandran et al., Lancet Oncol., 18(6):792-802 (2017)). [Overview of the project]

[0004] This specification provides methods and materials for evaluating and / or treating mammals (e.g., humans) with cancer (e.g., metastatic cancer). In some cases, this specification provides methods and materials for identifying whether cancer (e.g., metastatic cancer) is likely to respond to ACT, such as TIL therapy (e.g., by detecting the TIL score of the cancer). For example, this specification provides methods and materials for detecting the TIL score of cancer (e.g., metastatic cancer). In some cases, the TIL score is detectable in a sample from a mammal with cancer (e.g., metastatic cancer) (e.g., a tissue sample containing one or more cancer cells). For example, a sample taken from a mammal with cancer (e.g., metastatic cancer) can be evaluated, and at least in part, based on the TIL score of the sample, it can be determined whether the mammal is likely to respond to ACT (e.g., TIL therapy).

[0005] As shown herein, the nucleic acids listed in Table 1 express differently in distinct transcriptome signatures (e.g., pan-cancer transcriptome signatures) that can be used to calculate a TIL score that can indicate whether a mammal (e.g., human) is likely to respond to ACT (e.g., TIL therapy), regardless of the tumor's location and origin. For example, a core-like biopsy sample taken from a mammal (e.g., human) with cancer can be used to determine the TIL score of the cancer, thereby determining whether the cancer is likely to respond to ACT (e.g., TIL therapy). In some cases, the TIL score of a core-like biopsy taken from a mammal (e.g., human) with cancer (e.g., metastatic cancer) may be calculated based on the relative ranks of at least 30 (e.g., at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, or at least 250) of the nucleic acids listed in Table 1. Furthermore, as shown herein, a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6) may indicate that the cancer is responsive to ACT, such as TIL therapy. Once a mammal (e.g., human) is identified as having cancer responsive to ACT, such as TIL therapy, TILs can be collected from the mammal, grown ex vivo, and cultures of tumor-responsive TILs can be produced that can be administered to the mammal to treat the mammalian cancer.

[0006] The ability to determine whether a cancer (e.g., metastatic cancer) is likely to respond to an ACT (e.g., TIL therapy), as described herein (e.g., at least partially based on the cancer's TIL score), enables clinicians to evaluate identified patient populations in a less invasive, more efficient, and more accurate manner than current protocols. The ability to determine whether a cancer is likely to respond to an ACT (e.g., TIL therapy), as described herein (e.g., at least partially based on the cancer's TIL score), enables clinicians to provide an individualized approach in selecting cancer treatments, thereby improving disease-free survival and / or overall survival for identified patient populations. In addition, the ability to determine whether a cancer is likely to respond to an ACT (e.g., TIL therapy), as described herein (e.g., at least partially based on the cancer's TIL score), minimizes the administration of ineffective treatments to patients in identified patient populations. Furthermore, the methods provided herein enable more frequent sampling and allow clinicians to monitor tumor evolution (e.g., during treatment).

[0007] Generally, one aspect of this specification features a method for identifying mammals having cancers that are likely to respond to ACT. These methods include, or essentially consist of: (a) determining that a sample containing cancer cells taken from a mammal has a tumor-infiltrating lymphocyte score (TIL score) of at least 0.15, the TIL score being calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1; and (b) classifying the cancer as likely to respond to ACT. Mammals may be humans. ACT may include TIL therapy. Cancer may include solid tumors. The at least 30 nucleic acids listed in Table 1 may be at least 50 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may be at least 100 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may include at least 80% of the nucleic acids listed in Table 1 as having ranks #1 through #30. The at least 30 nucleic acids listed in Table 1 may include at least 90% of the nucleic acids listed in Table 1 as having ranks #1 through #30. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40.

[0008] In another embodiment, this specification features a method for identifying mammals with cancers that are unlikely to respond to ACT. The method includes, or may essentially consist of: (a) determining that a sample containing cancer cells taken from a mammal has a TIL score of less than 0.15, the TIL score being calculated based on the relative rank of a set of nucleic acids containing each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30; and (b) classifying the cancer as unlikely to respond to ACT. The mammal may be a human. ACT may include TIL therapy. Cancer may include solid tumors.

[0009] In another embodiment, this specification features a method for selecting a treatment for a mammal having cancer. The method includes, or may essentially consist of: (a) determining that a sample taken from a mammal having cancer and containing cancer cells has a TIL score of at least 0.15, the TIL score being calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1; and (b) selecting an ACT as a cancer treatment for the mammal. The mammal may be a human. The ACT may include TIL therapy. Cancer may include solid tumors. The at least 30 nucleic acids listed in Table 1 may be at least 50 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may be at least 100 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may include at least 80% of the nucleic acids listed in Table 1 as having ranks #1 through #30. The at least 30 nucleic acids listed in Table 1 may include at least 90% of the nucleic acids listed in Table 1 as having ranks #1 through #30. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40.

[0010] In another embodiment, this specification features a method for selecting a treatment for a mammal having cancer. The method includes, or may essentially consist of: (a) determining that a sample taken from a mammal having cancer and containing cancer cells has a TIL score of less than 0.15, the TIL score being calculated based on the relative rank of a set of nucleic acids, each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30; and (b) selecting a cancer treatment other than ACT for the mammal. The mammal may be a human. ACT may include TIL therapy. Cancer may include solid tumors. Cancer treatment may include radiotherapy. Cancer treatment may include the administration of anticancer agents selected from the group consisting of chemotherapy, targeted therapy, and angiogenesis inhibitors.

[0011] In another embodiment, this specification features a method for preparing treatment for a mammal having cancer. The method includes, or may essentially consist of: (a) determining that a sample taken from a mammal and containing cancer cells has a TIL score of at least 0.15, the TIL score being calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1; and (b) growing the TILs taken from the mammal ex vivo to obtain grown TILs for administration to the mammal. The mammal may be a human. Cancer may include solid tumors. The at least 30 nucleic acids listed in Table 1 may be at least 50 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may be at least 100 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may include at least 80% of the nucleic acids listed in Table 1 as having ranks #1 to #30. The at least 30 nucleic acids listed in Table 1 may include at least 90% of the nucleic acids listed in Table 1 as having ranks #1 to #30. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40. The method may also include administering at least a portion of the proliferating TILs to a mammal.

[0012] In another embodiment, this specification features a method for preparing a cancer treatment. The method may include, or essentially consist of: growing TILs taken from a mammal identified as having a TIL score of at least 0.15 to form a cell population for administration to the mammal to treat cancer, the TIL score being calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1. The mammal may be a human. Cancer may include solid tumors. The at least 30 nucleic acids listed in Table 1 may be at least 50 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may be at least 100 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may include at least 80% of the nucleic acids listed in Table 1 as having ranks #1 to #30. The at least 30 nucleic acids listed in Table 1 may include at least 90% of the nucleic acids listed in Table 1 as having ranks #1 to #30. The at least 30 nucleic acids listed in Table 1 may include at least 30 nucleic acids listed in Table 1 as having ranks #1 to #50. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 that have ranks #1 to #40. The method may also include administering at least a portion of the cell population to a mammal.

[0013] In another embodiment, this specification features a method for treating a mammal having cancer. The method includes, or may essentially consist of: (a) determining that a sample taken from a mammal and containing cancer cells has a TIL score of at least 0.15, calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1; and (b) administering ACT to the mammal. The mammal may be a human. ACT may include TIL therapy. Cancer may include solid tumors. The at least 30 nucleic acids listed in Table 1 may be at least 50 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may be at least 100 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may include at least 80% of the nucleic acids listed in Table 1 as having ranks #1 through #30. The at least 30 nucleic acids listed in Table 1 may include at least 90% of the nucleic acids listed in Table 1 as having ranks #1 through #30. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40.

[0014] In another embodiment, this specification features a method for treating cancer. The method may include, or essentially consist of: administering ACT to a mammal identified as having a TIL score of at least 0.15, the TIL score being determined from a sample taken from the mammal and containing cancer cells, and calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1. The mammal may be a human. ACT may include TIL therapy. Cancer may include solid tumors. The at least 30 nucleic acids listed in Table 1 may be at least 50 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may be at least 100 nucleic acids listed in Table 1. The at least 30 nucleic acids listed in Table 1 may include at least 80% of the nucleic acids listed in Table 1 as having ranks #1 through #30. The at least 30 nucleic acids listed in Table 1 may include at least 90% of the nucleic acids listed in Table 1 as having ranks #1 through #30. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50. The at least 30 nucleic acids listed in Table 1 may include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40.

[0015] In another embodiment, this specification features a method for treating a mammal having cancer. The method includes, or may essentially consist of: (a) determining that a sample taken from a mammal and containing cancer cells has a TIL score of less than 0.15, the TIL score being calculated based on the relative rank of a set of nucleic acids, each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30; and (b) administering a cancer treatment other than ACT to the mammal. The mammal may be a human. ACT may include TIL therapy. Cancer may include solid tumors. Cancer treatment may include performing surgery. Cancer treatment may include radiotherapy. Cancer treatment may include administering an anticancer agent selected from the group consisting of chemotherapy, targeted therapy, and angiogenesis inhibitors.

[0016] In another embodiment, this specification features a method for treating cancer. The method includes, or essentially consists of: administering a cancer treatment other than ACT to a mammal identified as having cancer cells having a TIL score less than 0.15, the TIL score being calculated based on the relative rank of a set of nucleic acids, each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30. The mammal may be a human. ACT may include TIL therapy. Cancer may include solid tumors. Cancer treatment may include the performance of surgery. Cancer treatment may include radiotherapy. Cancer treatment may include the administration of anticancer agents selected from the group consisting of chemotherapy, targeted therapy, and angiogenesis inhibitors.

[0017] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. The present invention can be carried out using methods and materials similar to or equivalent to those described herein, but suitable methods and materials are described below. All publications, patent applications, patents, and other references referenced herein are incorporated by reference in their entirety. In the event of any conflict, this specification, including definitions, shall prevail. Furthermore, the materials, methods, and examples are for illustrative purposes only and are not intended to be limiting.

[0018] Details relating to one or more embodiments of the present invention are described in the accompanying drawings and the following description. Other features, purposes and advantages of the present invention will become apparent from the description, drawings and claims. [Brief explanation of the drawing]

[0019] [Figure 1] A schematic diagram showing a comparison between the steps and time required to actually perform a current method for screening tumor tissue for TIL reactivity (left) and the steps and time required to perform an exemplary method of an exemplary embodiment provided herein (right). [Figure 2] This is a schematic diagram illustrating the development of the TIL score. [Figure 3]A pie chart showing the distribution of locations of resected metastatic foci of uveal melanoma used in the generation of the TIL score results provided in this specification. n = 100. [Figure 4] Heatmap of the correlation between principal components (PCs) and hallmark gene sets, and functional annotation of clusters (A, B, C, D). [Figure 5] Identification of the relationship between PC2 and cluster B. [Figure 6] Gene types in the PC2-immune axis gene list. [Figure 7] Functional annotation of genes in the PC2-immune axis gene list. [Figure 8] Pie charts of tumor tissue diagnoses in the validation cohort and the test cohort. [Figure 9] TIL score prediction ability in the training cohort, validation cohort, and test cohort. [Figure 10] The TIL score predicted TIL reactivity in a combined pan-cancer cohort. [Figure 11-1] Clinically relevant success: determination of the cut-off value for futility. The success: futility cut-off value was defined as the ability to generate tumor-reactive TIL cultures of ≥ 10% from a single metastatic focus in a gold standard laboratory assay. The graph shows the candidate gene set enrichment score (x-axis) using singscore against the percentage of tumor-reactive TIL cultures (y-axis) generated from 194 individual metastatic foci. The success: futility cut-off value is from the training + validation cohort of metastatic foci (n = 133) and represents the singscore enrichment value corresponding to a 25% probability of obtaining a significant tumor-reactive TIL culture (≥ 10). The dashed line and value represent the success: futility cut-off value overlaid on the total cohort of 194 individual metastatic foci. [Figure 11-2] Continuation of the above. [Figure 11-3] Continuation of the above. [Figure 12]The TIL score predicted the maximum percentage change in tumor size from the baseline of the response evaluation criteria for solid tumors (RECIST v1.1) in a sample of patients (n=42) who received TIL therapy. [Figure 13] In patients with refractory metastatic peritoneal mesothelioma, the TIL score predicts TIL responsiveness and response to TIL therapy. [Figure 14] The TIL score predicted improved overall survival after ACT in patients who received TIL therapy (n=19; TIL score response threshold: 0.235072296; upper = greater than, lower = less than or equal to). [Modes for carrying out the invention]

[0020] This specification provides methods and materials for evaluating and / or treating mammals (e.g., humans) with cancer (e.g., metastatic cancer). For example, this specification provides methods and materials for selectively treating mammals by identifying whether cancer (e.g., metastatic cancer) is likely to respond to ACT, such as TIL therapy (e.g., by determining the TIL score of the cancer). In some cases, the methods and materials described herein can be used to predict responsiveness to ACT (e.g., TIL therapy). For example, a sample from a mammal with cancer (e.g., metastatic cancer) (e.g., a tissue sample containing one or more cancer cells) can be evaluated, and it can be determined, at least partially based on the TIL score of the sample, whether the cancer is likely to respond to ACT (e.g., TIL therapy).

[0021] Once a mammal (e.g., human) is identified as having cancer responsive to an ACT described herein, such as TIL therapy, TILs can be collected from the mammal, grown ex vivo, and cultured to tumor-responsive TILs that can be administered to the mammal to treat the cancer. For example, a biopsy containing cancer cells can be taken from a mammal with cancer (e.g., human), and the TIL score of the cancer cells can be evaluated to determine whether the mammalian cancer is likely to respond to an ACT described herein (e.g., TIL therapy). If the TIL score of the cancer cells indicates that the mammalian cancer is likely to respond to an ACT (e.g., TIL therapy), then TILs collected from the mammal can be grown ex vivo to create cultured tumor-responsive TILs. Once these tumor-responsive TILs are obtained, they can be administered to the mammal to treat the mammalian cancer.

[0022] Any suitable method can be used to grow TILs (thickened leukocytes) in ex vivo from mammals (e.g., humans, or humans identified as having cancer responsive to ACT, such as TIL therapy, as described herein). In some cases, TILs can be grown in ex vivo by culturing them in the presence of one or more polypeptides that can promote the proliferation and / or differentiation of immune cells. Examples of polypeptides that can promote the proliferation and / or differentiation of immune cells and can be used to grow TILs in ex vivo include, but are not limited to, interleukin (IL)-2, IL-7, IL-15, IL-21, and anti-CD3 polypeptides (e.g., anti-CD3 antibodies). In some cases, TILs can be grown in ex vivo by culturing them in the presence of one or more IL-2 polypeptides and one or more anti-CD3 antibodies. In some cases, TILs can be grown in ex vivo as described elsewhere (e.g., Chandran et al., Lancet Oncol., 18: 792-802 (2017), page 794).

[0023] In some cases, the methods and materials described herein can predict the responsiveness to ACT in less than approximately two weeks (e.g., less than approximately one week, less than 14 days, less than 13 days, less than 12 days, less than 11 days, less than 10 days, less than 9 days, less than 8 days, less than 7 days, less than 6 days, less than 5 days, less than 4 days, or less than 4 days). For example, a sample from a mammal with cancer (e.g., metastatic cancer) (e.g., a tumor tissue sample) can be evaluated, and at least in part, it can be determined whether the cancer is likely to respond to ACT (e.g., TIL therapy) based on the TIL score of the cancer over a period of approximately two weeks (e.g., approximately two weeks to approximately one week, approximately two weeks to approximately five days, approximately five weeks to approximately two weeks, approximately one week to approximately two weeks, or approximately five weeks to approximately one week).

[0024] Mammals (e.g., humans) with cancer (e.g., metastatic cancer) can be evaluated by detecting the TIL score of the cancer to determine whether the cancer is likely to respond to ACT (e.g., TIL therapy). For example, a sample taken from a mammal with cancer (e.g., a tumor tissue sample) can be evaluated, and at least partially based on the TIL score of the cancer, it can be determined whether the mammal is likely to respond to ACT (e.g., TIL therapy). For example, the TIL score of a sample taken from a mammal with cancer (e.g., a tumor tissue sample) can be calculated to yield at least 30 nucleic acids (e.g., at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, or at least 250) as listed in Table 1 below. First, the nucleic acids are ranked in ascending order based on transcription levels for the elevated sets. Next, the mean ranks are individually normalized to the theoretical minimum and maximum values, centered around zero, and then summed to obtain a score (e.g., S) in the range of -1 to 1. total,i =S up,i +S down,iTo provide. In some cases, samples with high scores can be interpreted as having a transcriptome that matches the specified signature, and the score reflects the relative average percentile rank of the TIL score gene set within each sample. The score (S) and the normalized score (S) are defined as follows:

Number

Number

Number

[0025] In some cases, the maximum value is obtained by setting a1=(N total -N dir ):

number

[0026] Any suitable mammal having cancer (e.g., metastatic cancer) may be evaluated, prepared for treatment, and / or treated as described herein. Examples of mammals having cancer that may be evaluated, prepared for treatment, and / or treated as described herein include, but are not limited to, humans, non-human primates (e.g., monkeys), dogs, cats, horses, cattle, pigs, sheep, mice, and rats. In some cases, humans having cancer (e.g., metastatic cancer) may be evaluated, prepared for treatment, and / or treated as described herein.

[0027] When evaluating a mammal (e.g., human) having cancer as described herein, preparing a mammal (e.g., human) having cancer as described herein, and / or treating a mammal (e.g., human) having cancer as described herein, the cancer can be of any type. For example, the cancer evaluated and / or treated as described herein may include one or more solid tumors. In some cases, the cancer evaluated and / or treated as described herein may be a hematological cancer. In some cases, the cancer evaluated and / or treated as described herein may be a primary cancer. In some cases, the cancer evaluated and / or treated as described herein may be a metastatic cancer. In some cases, the cancer evaluated and / or treated as described herein may be a refractory cancer. In some cases, the cancer evaluated and / or treated as described herein may be a recurrent cancer. Examples of cancers that may be evaluated and / or treated as described herein include, but are not limited to, uveal melanoma, cutaneous melanoma, liver cancer, lung cancer, breast cancer, lymphoma, pancreatic cancer (e.g., pancreatic adenocarcinoma), spleen cancer, cholangiocarcinoma, mesothelioma (e.g., peritoneal mesothelioma), Merkel cell carcinoma, sarcoma, gastric cancer (e.g., gastric adenocarcinoma), mucosal melanoma, squamous cell carcinoma, colorectal adenocarcinoma, ovarian cancer, gastrointestinal stromal tumors, Merkel cell carcinoma, neuroendocrine tumors, urothelial carcinoma, eccrine porocarcinoma, paraganglioma, schwannoma, small intestinal adenocarcinoma, and solitary fibrous tumors. In some cases, a mammal (e.g., human) having cancer and being prepared (and optionally treated) as described herein may have multiple (e.g., two or more) different types of cancer. In some cases, a mammal (e.g., human) with cancer undergoing evaluation and / or preparation for treatment (and optionally treatment) as described herein may have cancer that has metastasized to one or more different sites.

[0028] In some cases, the methods described herein may include identifying a mammal (e.g., human) as having cancer (e.g., metastatic cancer). A mammal can be identified as having cancer using any suitable method. For example, imaging techniques and biopsy techniques can be used to identify a mammal (e.g., human) as having cancer.

[0029] In some cases, the TIL score used to determine whether cancer (e.g., metastatic cancer) is likely to respond to ACT (e.g., TIL therapy) can be calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1 (e.g., at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, or at least 250). For example, the TIL score of a sample taken from a mammal with cancer (e.g., a tumor tissue sample) can be calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1 (e.g., at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, or at least 250) to determine whether the cancer is likely to respond to ACT (e.g., TIL therapy). In some cases, if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1 (e.g., at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, or at least 250), is at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), the mammal can then be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy). In some cases, if the TIL score of cancer cells taken from a cancerous mammal (e.g., human), calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1, is less than 0.15, the mammal can then be identified as having cancer that is unlikely to respond to ACT (e.g., TIL therapy).

[0030] In some cases, a TIL score of at least 0.15 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 30 nucleic acids listed in Table 1 as having ranks #1 through #30, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). In some cases, a TIL score of at least 0.15 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 74 nucleic acids listed in Table 1 as having ranks #1 through #74, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). Similarly, if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 31 nucleic acids listed in Table 1 as having ranks #1 through #31, is at least 0.15, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy); if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 32 nucleic acids listed in Table 1 as having ranks #1 through #32, is at least 0.15, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy), and so on up to rank #74. In some cases, if the TIL score is not at least 0.15 in the examples of this paragraph, the mammal can then be identified as having cancer that is less likely to respond to ACT (e.g., TIL therapy).

[0031] In some cases, a TIL score of at least 0.16 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 75 nucleic acids listed in Table 1 as having ranks #1 through #75, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). In some cases, a TIL score of at least 0.16 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 89 nucleic acids listed in Table 1 as having ranks #1 through #89, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). Similarly, if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 76 nucleic acids listed in Table 1 as having ranks #1 through #76, is at least 0.16, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy), and if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 77 nucleic acids listed in Table 1 as having ranks #1 through #77, is at least 0.16, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy), and so on up to rank #89. In some cases, if the TIL score is not at least 0.16 in the examples of this paragraph, the mammal can then be identified as having cancer that is less likely to respond to ACT (e.g., TIL therapy).

[0032] In some cases, a TIL score of at least 0.17 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 90 nucleic acids listed in Table 1 as having ranks #1 through #90, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). In some cases, a TIL score of at least 0.17 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 95 nucleic acids listed in Table 1 as having ranks #1 through #95, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). Similarly, if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 91 nucleic acids listed in Table 1 as having ranks #1 through #91, is at least 0.17, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy); if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 92 nucleic acids listed in Table 1 as having ranks #1 through #92, is at least 0.17, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy), and so on up to rank #95. In some cases, if the TIL score is not at least 0.17 in the examples of this paragraph, the mammal can then be identified as having cancer that is less likely to respond to ACT (e.g., TIL therapy).

[0033] In some cases, a TIL score of at least 0.18 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 96 nucleic acids listed in Table 1 as having ranks #1 through #96, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). In some cases, a TIL score of at least 0.18 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 135 nucleic acids listed in Table 1 as having ranks #1 through #135, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). Similarly, if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 97 nucleic acids listed in Table 1 as having ranks #1 through #97, is at least 0.18, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy), and if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 98 nucleic acids listed in Table 1 as having ranks #1 through #98, is at least 0.18, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy), and so on up to rank #135. In some cases, if the TIL score is not at least 0.18 in the examples of this paragraph, the mammal can then be identified as having cancer that is less likely to respond to ACT (e.g., TIL therapy).

[0034] In some cases, a TIL score of at least 0.19 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 136 nucleic acids listed in Table 1 as having ranks #1 to #136, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). In some cases, a TIL score of at least 0.19 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 186 nucleic acids listed in Table 1 as having ranks #1 to #186, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). Similarly, if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 137 nucleic acids listed in Table 1 as having ranks #1 to #137, is at least 0.19, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy), and if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 138 nucleic acids listed in Table 1 as having ranks #1 to #138, is at least 0.19, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy), and so on up to rank #186. In some cases, if the TIL score is not at least 0.19 in the examples of this paragraph, the mammal can then be identified as having cancer that is less likely to respond to ACT (e.g., TIL therapy).

[0035] In some cases, a TIL score of at least 0.2 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 187 nucleic acids listed in Table 1 as having ranks #1 to #187, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). In some cases, a TIL score of at least 0.2 for cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of 265 nucleic acids listed in Table 1 as having ranks #1 to #265, can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy). Similarly, if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 188 nucleic acids listed in Table 1 as having ranks #1 to #188, is at least 0.2, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy), and if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of the 189 nucleic acids listed in Table 1 as having ranks #1 to #189, is at least 0.2, it can indicate that the mammal has cancer that is likely to respond to ACT (e.g., TIL therapy), and so on up to rank #265. In some cases, if the TIL score is not at least 0.2 in the examples of this paragraph, the mammal can then be identified as having cancer that is less likely to respond to ACT (e.g., TIL therapy).

[0036] In some cases, the TIL score used to determine whether cancer (e.g., metastatic cancer) is likely to respond to ACT (e.g., TIL therapy) may be calculated based on the relative ranks of at least 30% (e.g., at least 40%, at least 50%, at least 70%, at least 80%, or at least 90%) of the nucleic acids ranked #1 to #30 in Table 1. For example, the TIL score of a sample taken from a mammal with cancer (e.g., a tumor tissue sample) can be calculated based on the relative ranks of at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%) of the nucleic acids ranked #1 to #30 in Table 1 to determine whether the cancer is likely to respond to ACT (e.g., TIL therapy). In some cases, if cancer cells taken from a mammal with cancer (e.g., human) are determined to have a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), the mammal can then be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy). In some cases, if cancer cells taken from a mammal with cancer (e.g., human) are determined to have a TIL score of less than 0.15, the mammal can then be identified as having cancer that is unlikely to respond to ACT (e.g., TIL therapy). In some cases, the TIL score used to determine whether cancer (e.g., metastatic cancer) is likely to respond to ACT (e.g., TIL therapy) can be calculated based on the relative rank of each nucleic acid, ranked from #1 to #30 in Table 1. For example, the TIL score of a sample taken from a mammal with cancer (such as a tumor tissue sample) can be calculated based on the relative rank of each nucleic acid, which is ranked from #1 to #30 in Table 1, to determine whether the cancer is likely to respond to ACT (e.g., TIL therapy).In some cases, if cancer cells taken from a mammal with cancer (e.g., human) are determined to have a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), the mammal can then be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy).

[0037] In some cases, the TIL score used to determine whether cancer (e.g., metastatic cancer) is likely to respond to ACT (e.g., TIL therapy) may be calculated based on a relative rank of at least 9 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30). For example, the TIL score of a sample taken from a mammal with cancer (e.g., a tumor tissue sample) can be calculated based on a relative rank of at least 9 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30) to determine whether the cancer is likely to respond to ACT (e.g., TIL therapy). In some cases, if the TIL score of cancer cells taken from a mammal with cancer (e.g., human) is calculated based on the relative ranks of at least 9 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30) nucleic acids ranked as #1 to #30 in Table 1, and is at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), the mammal can then be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy).

[0038] In some cases, the TIL score used to determine whether a cancer (e.g., metastatic cancer) is likely to respond to ACT (e.g., TIL therapy) may be calculated based on the relative ranks of at least 50% (e.g., at least 60%, at least 70%, at least 80%, or at least 90%) of the nucleic acids ranked #1 to #60 in Table 1. For example, the TIL score of a sample taken from a mammal with cancer (e.g., a tumor tissue sample) can be calculated based on the relative ranks of at least 50% (e.g., at least 60%, at least 70%, at least 80%, or at least 90%) of the nucleic acids ranked #1 to #60 in Table 1 to determine whether the cancer in the mammal is likely to respond to ACT (e.g., TIL therapy). In some cases, if cancer cells taken from a mammal with cancer (e.g., human) are determined to have a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), the mammal can then be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy). For example, if the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%) of the nucleic acids ranked #1 to #30 in Table 1, and at least 60% (e.g., at least 70%, at least 80%, or at least 90%) of the nucleic acids ranked #31 to #60 in Table 1, is greater than at least 0.15, then the mammal can be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy).

[0039] In some cases, the TIL score used to determine whether cancer (e.g., metastatic cancer) is likely to respond to ACT (e.g., TIL therapy) may be calculated based on the relative ranks of at least 33.3% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%) of the nucleic acids ranked as #1 to #90 in Table 1. For example, the TIL score of a sample taken from a mammal with cancer (e.g., a tumor tissue sample) can be calculated based on the relative ranks of at least 33.3% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%) of the nucleic acids ranked as #1 to #90 in Table 1 to determine whether the cancer is likely to respond to ACT (e.g., TIL therapy). In some cases, if cancer cells taken from a mammal with cancer (e.g., human) are determined to have a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), the mammal can then be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy).For example, at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%) of the nucleic acids ranked #1 to #30 in Table 1, at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%) of the nucleic acids ranked #61 to #90 in Table 1, and at least 40% (e.g., at least 50%, at least If the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on a relative rank of 60%, at least 70%, at least 80%, or at least 90%, is at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), then the mammal can be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy).

[0040] In some cases, the TIL score used to determine whether cancer (e.g., metastatic cancer) is likely to respond to ACT (e.g., TIL therapy) is at least 9 nucleic acids ranked #1 to #30 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and at least 9 nucleic acids ranked #31 to #60 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 2 The ranking can be calculated based on the relative ranks of at least 9 nucleic acids ranked as #61 to #90 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and at least 3 nucleic acids ranked as #91 to #265 in Table 1 (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30). For example, the TIL score of a sample taken from a mammal with cancer (e.g., a tumor tissue sample) can be calculated based on the relative ranks of at least 9 nucleic acids ranked #1 to #30 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30) and at least 21 nucleic acids ranked #31 to #265 in Table 1 (e.g., at least 22, 23, 24, 25, 26, 27, 28, 29, or 30) to determine whether the cancer is likely to respond to ACT (e.g., TIL therapy).In some cases, the calculation is based on the relative ranks of at least 9 nucleic acids ranked #1 to #30 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30) and at least 21 nucleic acids ranked #31 to #265 in Table 1 (e.g., at least 22, 23, 24, 25, 26, 27, 28, 29, or 30). If the TIL score of cancer cells taken from a mammal with cancer (e.g., human) is at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), then the mammal can be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy).

[0041] In some cases, the TIL score used to determine whether cancer (e.g., metastatic cancer) is likely to respond to ACT (e.g., TIL therapy) is at least 9 nucleic acids ranked #1 to #30 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and nucleic acids ranked #31 to #60 in Table 1. This can be calculated based on the relative ranks of at least 9 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30) of nucleic acids ranked as #61 to #265 in Table 1. For example, the TIL score of a sample taken from a mammal with cancer (e.g., a tumor tissue sample) is determined by at least 9 nucleic acids ranked as #1 to #30 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and at least 9 nucleic acids ranked as #31 to #60 in Table 1 (e.g., at least 10, 11, 12, 13, 14 Based on the relative ranks of at least 12 nucleic acids (e.g., at least 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) ranked as #61 to #265 in Table 1, it is possible to determine whether the cancer is likely to respond to ACT (e.g., TIL therapy).In some cases, at least 9 nucleic acids ranked #1 to #30 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), at least 9 nucleic acids ranked #31 to #60 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and at least 12 nucleic acids ranked #61 to #265 in Table 1 (e.g., at least 1 If the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on a relative rank of 3, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30), is at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), then the mammal can be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy).

[0042] In some cases, the TIL score used to determine whether cancer (e.g., metastatic cancer) is likely to respond to ACT (e.g., TIL therapy) is at least 9 nucleic acids ranked #1 to #30 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and at least 9 nucleic acids ranked #31 to #60 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 2 The ranking can be calculated based on the relative ranks of at least 9 nucleic acids ranked as #61 to #90 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and at least 3 nucleic acids ranked as #91 to #265 in Table 1 (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30).For example, the TIL score of a sample taken from a mammal with cancer (e.g., tumor tissue sample) is ranked as follows: at least 9 nucleic acids ranked as #1 to #30 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and at least 9 nucleic acids ranked as #31 to #60 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and #61 to # Based on the relative ranks of at least 9 nucleic acids ranked as 90 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30) and at least 3 nucleic acids ranked as #91 to #265 in Table 1 (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30), it is possible to determine whether the cancer is likely to respond to ACT (e.g., TIL therapy).In some cases, at least 9 nucleic acids ranked #1 to #30 in Table 1 (e.g., at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and at least 9 nucleic acids ranked #31 to #60 in Table 1 (e.g., at least 10, 11, 12, 1 3, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), at least 9 nucleic acids ranked as #61 to #90 in Table 1 (for example, at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all 30), and Table 1 If the TIL score of cancer cells taken from a mammal with cancer (e.g., human), calculated based on the relative ranks of at least three nucleic acids (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) ranked as #91 to #265 in the , is at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), then the mammal can be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy).

[0043] In some cases, the TIL score used to determine whether a cancer (e.g., metastatic cancer) is likely to respond to ACT (e.g., TIL therapy) may be calculated based on the relative ranks of at least 30 nucleic acids ranked as #1 to #265 in Table 1 (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, or all 265). For example, the TIL score of a sample taken from a mammal with cancer (e.g., a tumor tissue sample) is ranked as follows: at least 30 nucleic acids (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, Based on the relative ranks of 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, or all 265, it is possible to determine whether the cancer is likely to respond to ACT (e.g., TIL therapy).In some cases, at least 30 nucleic acids ranked as #1 to #265 in Table 1 (e.g., 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, or all Based on the relative ranks in 265), if the TIL score of cancer cells taken from a mammal with cancer (e.g., human) is at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), the mammal can be identified as having cancer that is likely to respond to ACT (e.g., TIL therapy).

[0044] A suitable sample from a mammal (e.g., human) with cancer (e.g., metastatic cancer) can be evaluated as described herein (e.g., by measuring the TIL score of cancer). In some cases, the sample may be a biological sample. In some cases, the sample may contain one or more cancer cells. In some cases, the sample may contain one or more biological molecules (e.g., nucleic acids such as DNA and RNA, polypeptides, carbohydrates, lipids, hormones, and / or metabolites). Examples of samples that can be evaluated as described herein include, but are not limited to, tissue samples, such as tumor tissue samples (e.g., tumor fragments) and tumor single-cell suspensions. The sample may be a fresh sample (e.g., a fresh-frozen sample). In some cases, one or more biological molecules can be isolated from the sample (e.g., from one or more cancer cells in the sample). For example, nucleic acids can be isolated from the sample and evaluated as described herein.

[0045] Samples (e.g., tumor tissue samples) can be collected from mammals (e.g., humans) with cancer (e.g., metastatic cancer) using any appropriate method. In some cases, samples can be collected using core biopsy or core-like biopsy.

[0046] In some cases, samples (e.g., tumor tissue samples) can be obtained from mammals (e.g., humans) with cancer (e.g., metastatic cancer) without surgery.

[0047] In some cases, a TIL score for cancer (e.g., metastatic cancer) can be used to identify cancers that are likely to respond to ACT (e.g., TIL therapy). For example, a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6) in a sample (e.g., tumor tissue sample) taken from a mammal (e.g., human) with cancer, calculated based on relative rank, can be used to identify cancers (e.g., metastatic cancer) in mammals (e.g., humans) that are likely to respond to ACT (e.g., TIL therapy).

[0048] In some cases, the TIL score of cancer (e.g., metastatic cancer) can be used to identify cancers that are unlikely to respond to ACT (e.g., TIL therapy). For example, a TIL score of less than 0.15 in a sample (e.g., tumor tissue sample) taken from a mammal (e.g., human) with cancer (e.g., metastatic cancer) can be used to identify cancers that are unlikely to respond to ACT (e.g., TIL therapy).

[0049] In some cases, mammals (e.g., humans) with cancer (e.g., metastatic cancer) identified as likely to respond to ACT (e.g., TIL therapy) as described herein (e.g., at least in part based on the cancer's TIL score) may be selected to receive ACT (e.g., TIL therapy) to treat the cancer. For example, mammals with cancer (e.g., metastatic cancer) identified with a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6) may be selected to receive ACT (e.g., TIL therapy).

[0050] In some cases, mammals (e.g., humans) with cancer (e.g., metastatic cancer) identified as unlikely to respond to the ACTs (e.g., TIL therapy) described herein may be selected for alternative cancer treatments (e.g., one or more cancer treatments other than ACTs) to treat the cancer. For example, mammals with cancer (e.g., metastatic cancer) identified as having a TIL score of less than 0.15 may be selected for alternative cancer treatments (e.g., one or more cancer treatments other than ACTs).

[0051] This specification also provides methods and materials for treating mammals (e.g., humans) having cancer (e.g., metastatic cancer). In some cases, a mammal (e.g., human) having cancer and being evaluated as described herein (e.g., to determine whether the cancer is likely to respond to an ACT, such as TIL therapy, at least in part based on the cancer's TIL score) may be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) cancer treatments, one or more of which are effective in treating cancer in the mammal. For example, a mammal having cancer may be administered or instructed to self-administer one or more cancer treatments selected at least in part based on whether the cancer is likely to respond to an ACT, such as TIL therapy (e.g., at least in part based on the cancer's TIL score).

[0052] When treating mammals (e.g., humans) with cancer (e.g., metastatic cancer) identified as likely to respond to ACT (e.g., TIL therapy) as described herein, the mammals may be administered ACT or instructed to self-administer it. For example, a mammal with cancer (e.g., metastatic cancer) identified as having a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6) may be administered one or more ACT or instructed to self-administer it. Examples of ACTs that can be administered to mammals (e.g., humans) with cancer (e.g., metastatic cancer) identified as likely to respond to ACT as described herein include, but are not limited to, TIL therapy.

[0053] When treating a mammal (e.g., human) with cancer (e.g., metastatic cancer) that has been identified as having a low response to ACT (e.g., TIL therapy) as described herein (e.g., based at least partially on the cancer's TIL score), the mammal may be instructed to administer or self-administer one or more (e.g., one, two, three, four, five, or more) alternative cancer treatments (e.g., one or more cancer treatments other than ACT, e.g., TIL therapy). For example, a mammal with cancer (e.g., metastatic cancer) that has been determined to have a TIL score of less than 0.15 may be instructed to administer or self-administer one or more alternative cancer treatments other than ACT (e.g., TIL therapy). Examples of alternative cancer treatments other than ACT (e.g., TIL therapy) include, but are not limited to, surgery, radiotherapy, and administration of one or more anticancer agents (e.g., chemotherapy, targeted therapy (e.g., monoclonal antibody therapy), and angiogenesis inhibitors).

[0054] In some cases, when treating a mammal (e.g., human) with cancer (e.g., metastatic cancer) as described herein, the treatment may be effective in treating the cancer. For example, the methods and materials described herein can be used to reduce the number of cancer cells present in a mammal. In some cases, the methods and materials described herein can be used to reduce the size (e.g., volume) of one or more tumors present in a mammal. For example, the methods and materials described herein can reduce the size of one or more tumors present in a mammal with cancer (e.g., metastatic cancer) to, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, the methods and materials described herein can be used to treat cancer so as not to increase the size (e.g., volume) of one or more tumors present in a mammal.

[0055] In some cases, when treating mammals (e.g., humans) with cancer (e.g., metastatic cancer) as described herein, the treatment may be effective in improving the survival of the mammals. For example, the methods and materials described herein are used to improve disease-free survival (e.g., recurrence-free survival). For example, the methods and materials described herein can be used to improve progression-free survival. For example, the methods and materials described herein can be used to improve the survival of mammals with cancer (e.g., metastatic cancer) by, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more. For example, the methods and materials described herein can be used to improve the survival of mammals with cancer (e.g., metastatic cancer) by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, or about 3 years).

[0056] The present invention is further described in the following embodiments. These embodiments do not limit the scope of the invention as described in the claims. [Examples]

[0057] Example 1: Transcriptome-guided tumor-infiltrating lymphocyte (TIL) therapy This embodiment describes the identification of a pan-cancerous transcriptome signature (TIL score) that can be used to predict whether a tumor is likely to respond to adoptive cell therapy (e.g., TIL therapy).

[0058] A typical method used to identify nucleic acids and generate a TIL score is shown in Figure 2.

[0059] Development of TIL score Discovery cohort Uveal melanoma is a cancer with low immunogenicity. 100 metastatic lesions of uveal melanoma were surgically removed from 84 patients, and 12 patients underwent multiple tumor biopsies. The locations of the collected metastatic lesions are shown in Figure 3. The median age of the patients was 56 years, with 52% being female and 48% male. The median tumor mutational burden (TMB) was 0.64 mutations / million base pairs. 46 out of 84 patients had previously undergone checkpoint inhibition. None of the patients were responders to checkpoint inhibition.

[0060] Tissue samples were obtained from the tumor using core-like biopsies to acquire 2-3 mm size samples. The samples were rapidly frozen until analysis was performed. The collected tissue samples were also subjected to TIL proliferation and immunological investigations using current methods.

[0061] Total RNA sequencing was performed on collected tissue samples for both coding and non-coding RNAs. Approximately 40 million reads were obtained per sample, and counts were acquired using a custom, static bioinformatics pipeline.

[0062] Principal component analysis (PCA) To determine the principal components (PCs) that contribute significantly to the variance, a 10% variance threshold was used. Only those contributing ≥10% of the variance were considered relevant (PC1, PC2, PC3).

[0063] To correlate established biological signatures with principal components, enrichment scores were calculated using singscore for samples from the MSigDB Hallmark gene set collection, and these scores were correlated with principal component sample loadings. The principal component correlations with the Hallmark gene sets are shown in Figure 4. Functional characterization of clusters was performed based on the gene sets contained within each cluster (Figure 4). Specific principal component-cluster relationships were tested using mean rho (Figure 5). Cluster A (cellular metabolism) was strongly correlated with PC3 (mean rho = +0.76) but also weakly negatively correlated with PC1 (mean rho = -0.27) (Figure 5). Cluster B (immune and inflammatory signaling) was negatively correlated only with PC2 (mean rho = -0.32) (Figure 5). Clusters C and D were not found to be independently correlated with any of the three principal components (Figure 5).

[0064] To investigate PC2, a notable principal component that provides a specific correlation with the immunogene set, gene loadings for PC2 were examined, and the gene contributions to positive or negative PC3 were identified. 2394 notable genes were identified that correlated with PC2 in the same direction as the Hallmark immunogene set. Gene type and functional annotations were shown for coding and non-coding genes (Figure 6), as well as immune-related functions (Figure 7).

[0065] The PC2 immunogene list (n=2394) was subjected to a singscore method using transcripts per million inputs (TPM) to obtain a rank-based approach, resulting in a single score per sample with enrichment scores ranging from 0 to 1.

[0066] Verification and application of TIL score Multihistology analysis To determine whether the list of 2394 genes could predict TIL reactivity in other immunogenic solid tumors, 94 samples representing multiple different solid tumor types were obtained (Figure 8). Immunological studies and RNA-seq+TIL scores were applied to these samples. Genes were ranked by the strength of their correlation with immunological TIL reactivity in a training cohort (100 uveal melanomas). Subsequently, the list of 2394 genes was sequentially shaved from the weakest to the strongest correlations to test the ability of each gene set to predict TIL reactivity in the training and validation cohorts. Based on the strongest combined predictive value in the validation cohort, 265 gene sets (Table 1) were selected and named the TIL score. The TIL score correlated with TIL reactivity and was successfully classified into training, validation, and independent trial cohorts (Figure 9). By combining metastatic uveal malignant melanoma samples with multihtological samples, a pan-cancer cohort was generated (Figure 10), and TIL score analysis was performed. The TIL score correlated with TIL responsiveness in the combined pan-cancer cohort, and we were able to successfully classify it (Figure 10).

[0067] The TIL score can guide the selection of the harvest site. To determine whether the TIL score can identify metastatic sites and guide the selection of harvest sites preoperatively, we created a TIL score responsiveness probability calculator using the following formula:

number

[0068] To determine whether the TIL score can predict the clinical efficacy of TIL after ACT, RNA sequencing and the TIL score were applied to uveal melanoma samples obtained from 42 patients who received TIL therapy. The TIL score predicted the RECIST response in these patients who received TIL therapy (Figure 12). These results demonstrate that the TIL score, based on scores generated from pre-treatment core biopsy or core-like biopsy and transcriptome profiling, predicted the clinical response of TIL to ACT.

[0069] The TIL score predicts TIL responsiveness in cancers with low immunogenicity. To determine whether the TIL score is clinically applicable to other less immunogenic cancers, the TIL score was calculated from a sample of a patient with refractory peritoneal mesothelioma (a 60-year-old woman with metastatic malignant peritoneal mesothelioma). The patient had previously been treated with the following, and experienced recurrence or progression with all of these treatments: 1) pemetrexed and cisplatin, 2) CRS / HIPEC with mitomycin C (with pemetrexed and carboplatin as adjuvant agents), 3) right thoracotomy and debulking of the right chest (with pemetrexed and carboplatin as adjuvant agents), 4) radiotherapy (5000 cGy to paraesophageal lymph nodes), 5) palliative small bowel bypass with terminal colostomy, 6) anti-PD-1 therapy, and / or 7) anti-CTLA-4 + anti-PD-1 therapy. The TIL score was found to be 0.297, and the probability of TIL responsiveness was found to be 60.7%. The TIL score predicted TIL responsiveness and ACT response in this patient with refractory peritoneal mesothelioma (Figure 13).

[0070] Example 2: Top 265 nucleic acids used to generate TIL scores Nucleic acids were ranked in order of their contribution to effectively determining whether cancer is likely to respond to ACTs such as TIL therapy (Table 1).

[0071] [Table 1] TIFF2026520000000008.tif236163TIFF2026520000000009.tif236163TIFF2026520000000010.tif236163TIFF2026520000000011.tif98163

[0072] Example 3: Gene ID numbers of the top 265 nucleic acids for humans used to generate the TIL score. The HUGO Gene Nomenclature Committee gene ID (HGNC_ID) numbers for each nucleic acid listed in Table 1 for humans are as shown in Table 2.

[0073] [Table 2] TIFF2026520000000013.tif236164TIFF2026520000000014.tif236164TIFF2026520000000015.tif236164TIFF2026520000000016.tif94164

[0074] Example 4: Evaluation of gene sets of different sizes To assess the performance of candidate gene sets, standardized, clinically relevant success:useless cutoff values ​​were evaluated for the selected gene sets. The success:useless cutoff value was defined as the ability to generate approximately 10% tumor-responsive TIL cultures from a single metastatic lesion in a gold-standard laboratory assay. The graph in Figure 11 shows the enrichment score (x-axis) of the candidate gene sets using singscore against the percentage of tumor-responsive TIL cultures (y-axis) generated from 194 individual metastatic lesions.

[0075] The success / failure cutoff value was derived from the training + validation cohort of metastatic lesions (n=133) and represents the singscore enrichment value corresponding to a 25% probability of obtaining significant tumor-responsive TIL cultures (approximately 10%). The dashed line and numbers in Figure 11 represent the success / failure cutoff value superimposed on the entire cohort of 194 individual metastatic lesions.

[0076] Example 5: Evaluation of cancer based on TIL reactivity A tumor tissue sample is obtained from a person with cancer (e.g., metastatic cancer). The obtained sample is evaluated, and the TIL score of the sample is calculated based on the relative rank of at least 80% (e.g., at least 90%, or 100%) of the 30 nucleic acids listed in Table 1, which are assigned ranks #1 to #30.

[0077] If a sample has a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), the cancer is subsequently classified as responsive to ACT (e.g., TIL therapy).

[0078] If a sample has a TIL score of less than 0.15, the cancer is subsequently classified as unresponsive to ACT (e.g., TIL therapy).

[0079] Example 6: Preparation of treatment for a person with cancer A tumor tissue sample is obtained from a person with cancer (e.g., metastatic cancer). The obtained sample is evaluated, and the TIL score of the sample is calculated based on the relative rank of at least 80% (e.g., at least 90%, or 100%) of the 30 nucleic acids listed in Table 1, which are assigned ranks #1 to #30.

[0080] If a sample has a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), the TILs obtained from humans are then grown ex vivo. After growth, the TILs are formulated into compositions for administration to humans to treat human cancer.

[0081] If a sample has a TIL score of less than 0.15, preparation for TIL for humans can be avoided or discontinued, and other cancer treatments can be considered.

[0082] Example 7: Cancer treatment A tumor tissue sample is obtained from a person with cancer (e.g., metastatic cancer). The obtained sample is evaluated, and the TIL score of the sample is calculated based on the relative rank of at least 80% (e.g., at least 90%, or 100%) of the 30 nucleic acids listed in Table 1, which are assigned ranks #1 to #30.

[0083] If a sample has a TIL score of at least 0.15 (e.g., at least 0.15, at least 0.16, at least 0.17, at least 0.18, at least 0.19, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 0.6), the TILs obtained from humans are then grown ex vivo. After growth, the TILs are formulated into a composition for administration to humans, and the formulated composition is administered to humans. After administration to humans, the TILs can reduce the number of cancer cells present in the human body.

[0084] Example 8: Treatment of cancer A tumor tissue sample is obtained from a person with cancer (e.g., metastatic cancer). The obtained sample is evaluated, and the TIL score of the sample is calculated based on the relative rank of at least 80% (e.g., at least 90%, or 100%) of the 30 nucleic acids listed in Table 1, which are assigned ranks #1 to #30.

[0085] If a sample has a TIL score of less than 0.15, the person may receive one or more alternative cancer treatments (e.g., one, two, three, four, five, or more) (e.g., one or more non-ACT cancer treatments such as TIL therapy). Alternative cancer treatments can reduce the number of cancer cells present in the person.

[0086] Other embodiments Although the present invention is described in conjunction with the detailed description of the invention, the above description is intended to illustrate, not limit, the scope of the invention, and it should be understood that the scope of the invention is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A method for identifying mammals with cancer likely to respond to adoptive cell therapy (ACT), comprising the following steps: (a) A step of determining whether a sample containing cancer cells obtained from the mammal has a tumor-infiltrating lymphocyte score (TIL score) of at least 0.15, wherein the TIL score is calculated based on the relative rank of at least 30 nucleic acids listed in Table 1; and (b) A step of classifying the cancer as one that is likely to respond to the ACT.

2. The method according to claim 1, wherein the mammal is a human.

3. The method according to any one of claims 1 to 2, wherein the ACT comprises tumor-infiltrating lymphocyte (TIL) therapy.

4. The method according to any one of claims 1 to 3, wherein the cancer includes a solid tumor.

5. The method according to any one of claims 1 to 4, wherein the at least 30 nucleic acids listed in Table 1 are the at least 50 nucleic acids listed in Table 1.

6. The method according to any one of claims 1 to 4, wherein the at least 30 nucleic acids listed in Table 1 are the at least 100 nucleic acids listed in Table 1.

7. The method according to any one of claims 1 to 6, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 80% of the nucleic acids listed in Table 1, having ranks #1 to #30.

8. The method according to any one of claims 1 to 6, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 90% of the nucleic acids listed in Table 1, having ranks #1 to #30.

9. The method according to any one of claims 1 to 8, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50.

10. The method according to any one of claims 1 to 8, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40.

11. A method for identifying mammals with cancer that is unlikely to respond to ACT, comprising the following steps: (a) A step of determining whether a sample containing cancer cells obtained from the mammal has a TIL score of less than 0.15, wherein the TIL score is calculated based on the relative rank of a set of nucleic acids, each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30; and (b) A step of classifying the cancer as unlikely to respond to the ACT.

12. The method according to claim 11, wherein the mammal is a human.

13. The method according to any one of claims 11 to 12, wherein the ACT includes TIL therapy.

14. The method according to any one of claims 11 to 13, wherein the cancer includes a solid tumor.

15. A method for selecting a treatment for a mammal with cancer, comprising the following steps: (a) A step of determining that a sample containing cancer cells obtained from the mammal has a TIL score of at least 0.15, wherein the TIL score is calculated based on the relative rank of at least 30 nucleic acids listed in Table 1; and (b) The step of selecting ACT as a treatment for cancer in the mammal.

16. The method according to claim 15, wherein the mammal is a human.

17. The method according to any one of claims 15 to 16, wherein the ACT includes TIL therapy.

18. The method according to any one of claims 15 to 17, wherein the cancer includes a solid tumor.

19. The method according to any one of claims 15 to 18, wherein the at least 30 nucleic acids listed in Table 1 are the at least 50 nucleic acids listed in Table 1.

20. The method according to any one of claims 15 to 18, wherein the at least 30 nucleic acids listed in Table 1 are the at least 100 nucleic acids listed in Table 1.

21. The method according to any one of claims 15 to 20, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 80% of the nucleic acids listed in Table 1, having ranks #1 to #30.

22. The method according to any one of claims 15 to 20, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 90% of the nucleic acids listed in Table 1, having ranks #1 to #30.

23. The method according to any one of claims 15 to 22, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50.

24. The method according to any one of claims 15 to 22, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40.

25. A method for selecting a treatment for a mammal with cancer, comprising the following steps: (a) A step of determining whether a sample containing cancer cells obtained from the mammal has a TIL score of less than 0.15, wherein the TIL score is calculated based on the relative rank of a set of nucleic acids, each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30; and (b) A step of selecting a cancer treatment other than ACT for the mammal.

26. The method according to claim 25, wherein the mammal is a human.

27. The method according to any one of claims 25 to 26, wherein the ACT includes TIL therapy.

28. The method according to any one of claims 25 to 27, wherein the cancer includes a solid tumor.

29. The method according to any one of claims 25 to 28, wherein the treatment of the cancer includes radiotherapy.

30. The method according to any one of claims 25 to 28, wherein the treatment of the cancer comprises administering an anticancer agent selected from the group consisting of chemotherapy, targeted therapy, and angiogenesis inhibitors.

31. A method for preparing treatment for a mammal with cancer, comprising the following steps: (a) A step of determining that a sample containing cancer cells obtained from the mammal has a TIL score of at least 0.15, wherein the TIL score is calculated based on the relative rank of at least 30 nucleic acids listed in Table 1; and (b) A step of growing the TIL obtained from the mammal ex vivo to obtain grown TIL for administration to the mammal.

32. The method according to claim 31, wherein the mammal is a human.

33. The method according to any one of claims 31 to 32, wherein the cancer includes a solid tumor.

34. The method according to any one of claims 31 to 33, wherein the at least 30 nucleic acids listed in Table 1 are the at least 50 nucleic acids listed in Table 1.

35. The method according to any one of claims 31 to 33, wherein the at least 30 nucleic acids listed in Table 1 are the at least 100 nucleic acids listed in Table 1.

36. The method according to any one of claims 31 to 35, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 80% of the nucleic acids listed in Table 1, having ranks #1 to #30.

37. The method according to any one of claims 31 to 35, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 90% of the nucleic acids listed in Table 1, having ranks #1 to #30.

38. The method according to any one of claims 31 to 37, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50.

39. The method according to any one of claims 31 to 37, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40.

40. The method according to any one of claims 31 to 39, further comprising administering at least a portion of the proliferating TIL to the mammal.

41. A method for preparing a cancer treatment, comprising the step of growing TILs obtained from a mammal identified as having a TIL score of at least 0.15 to form a cell population for administration to the mammal to treat cancer, wherein the TIL score is calculated based on the relative rank of at least 30 nucleic acids listed in Table 1.

42. The method according to claim 41, wherein the mammal is a human.

43. The method according to any one of claims 41 to 42, wherein the cancer includes a solid tumor.

44. The method according to any one of claims 41 to 43, wherein the at least 30 nucleic acids listed in Table 1 are the at least 50 nucleic acids listed in Table 1.

45. The method according to any one of claims 41 to 43, wherein the at least 30 nucleic acids listed in Table 1 are the at least 100 nucleic acids listed in Table 1.

46. The method according to any one of claims 41 to 45, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 80% of the nucleic acids listed in Table 1, having ranks #1 to #30.

47. The method according to any one of claims 41 to 45, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 90% of the nucleic acids listed in Table 1, having ranks #1 to #30.

48. The method according to any one of claims 41 to 47, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50.

49. The method according to any one of claims 41 to 47, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40.

50. The method according to any one of claims 41 to 49, further comprising administering at least a portion of the cell population to the mammal.

51. A method for treating a mammal with cancer, comprising the following steps: (a) A step of determining that a sample containing cancer cells obtained from the mammal has a TIL score of at least 0.15, wherein the TIL score is calculated based on the relative rank of at least 30 nucleic acids listed in Table 1; and (b) The step of administering ACT to the mammal.

52. The method according to claim 51, wherein the mammal is a human.

53. The method according to any one of claims 51 to 52, wherein the ACT includes TIL therapy.

54. The method according to any one of claims 51 to 53, wherein the cancer includes a solid tumor.

55. The method according to any one of claims 51 to 54, wherein the at least 30 nucleic acids listed in Table 1 are the at least 50 nucleic acids listed in Table 1.

56. The method according to any one of claims 51 to 54, wherein the at least 30 nucleic acids listed in Table 1 are the at least 100 nucleic acids listed in Table 1.

57. The method according to any one of claims 51 to 56, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 80% of the nucleic acids listed in Table 1, having ranks #1 to #30.

58. The method according to any one of claims 51 to 56, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 90% of the nucleic acids listed in Table 1, having ranks #1 to #30.

59. The method according to any one of claims 51 to 58, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50.

60. The method according to any one of claims 51 to 58, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40.

61. A method for treating cancer, comprising the step of administering ACT to a mammal identified as having a TIL score of at least 0.15, wherein the TIL score is determined from a sample containing cancer cells obtained from the mammal, and the TIL score is calculated based on the relative ranks of at least 30 nucleic acids listed in Table 1.

62. The method according to claim 61, wherein the mammal is a human.

63. The method according to any one of claims 61 to 62, wherein the ACT includes TIL therapy.

64. The method according to any one of claims 61 to 63, wherein the cancer includes a solid tumor.

65. The method according to any one of claims 61 to 64, wherein the at least 30 nucleic acids listed in Table 1 are the at least 50 nucleic acids listed in Table 1.

66. The method according to any one of claims 61 to 64, wherein the at least 30 nucleic acids listed in Table 1 are the at least 100 nucleic acids listed in Table 1.

67. The method according to any one of claims 61 to 66, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 80% of the nucleic acids listed in Table 1, having ranks #1 to #30.

68. The method according to any one of claims 61 to 66, wherein the at least 30 nucleic acids listed in Table 1 comprise at least 90% of the nucleic acids listed in Table 1, having ranks #1 to #30.

69. The method according to any one of claims 61 to 68, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #50.

70. The method according to any one of claims 61 to 68, wherein the at least 30 nucleic acids listed in Table 1 include the at least 30 nucleic acids listed in Table 1 having ranks #1 to #40.

71. A method for treating a mammal with cancer, comprising the following steps: (a) A step of determining whether a sample containing cancer cells obtained from the mammal has a TIL score of less than 0.15, wherein the TIL score is calculated based on the relative rank of a set of nucleic acids, each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30. (b) The step of administering a cancer treatment other than ACT to the mammal.

72. The method according to claim 71, wherein the mammal is a human.

73. The method according to any one of claims 71 to 72, wherein the ACT includes TIL therapy.

74. The method according to any one of claims 71 to 73, wherein the cancer includes a solid tumor.

75. The method according to any one of claims 71 to 74, wherein the cancer treatment includes performing a surgical procedure.

76. The method according to any one of claims 71 to 75, wherein the cancer treatment includes radiotherapy.

77. The method according to any one of claims 71 to 76, wherein the cancer treatment comprises the administration of an anticancer agent selected from the group consisting of chemotherapy, targeted therapy, and angiogenesis inhibitors.

78. A method for treating cancer, comprising the step of administering a cancer treatment other than ACT to a mammal identified as having cancer cells with a TIL score of less than 0.15, wherein the TIL score is calculated based on the relative rank of a set of nucleic acids, each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30.

79. The method according to claim 78, wherein the mammal is a human.

80. The method according to any one of claims 78 to 79, wherein the ACT includes TIL therapy.

81. The method according to any one of claims 78 to 80, wherein the cancer includes a solid tumor.

82. The method according to any one of claims 78 to 81, wherein the cancer treatment includes performing a surgical procedure.

83. The method according to any one of claims 78 to 82, wherein the cancer treatment includes radiotherapy.

84. The method according to any one of claims 78 to 83, wherein the cancer treatment comprises administering an anticancer agent selected from the group consisting of chemotherapy, targeted therapy, and angiogenesis inhibitors.

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