EP4713489A2 - Verfahren und materialien zur beurteilung und behandlung von krebs - Google Patents

Verfahren und materialien zur beurteilung und behandlung von krebs

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Publication number
EP4713489A2
EP4713489A2 EP24807720.8A EP24807720A EP4713489A2 EP 4713489 A2 EP4713489 A2 EP 4713489A2 EP 24807720 A EP24807720 A EP 24807720A EP 4713489 A2 EP4713489 A2 EP 4713489A2
Authority
EP
European Patent Office
Prior art keywords
nucleic acids
cancer
rank
acids listed
mammal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24807720.8A
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English (en)
French (fr)
Inventor
Udai Shankar KAMMULA
Shravan LEONARD-MURALI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Pittsburgh
Original Assignee
University of Pittsburgh
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Filing date
Publication date
Application filed by University of Pittsburgh filed Critical University of Pittsburgh
Publication of EP4713489A2 publication Critical patent/EP4713489A2/de
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
    • G01N33/5759—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites involving compounds localised on the membrane of tumour or cancer cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • methods and materials provided herein can be used to identify a cancer (e.g., metastatic cancer) as being likely to respond to an adoptive cell therapy (ACT; e.g., a tumor infiltrating lymphocyte (TIL) therapy).
  • ACT adoptive cell therapy
  • methods and materials provided herein can be used to treat a mammal (e.g., a human) having cancer (e.g., metastatic cancer) where the cancer treatment is selected based on whether or not the cancer is likely to be responsive to an ACT (e.g., a TIL therapy).
  • ACT adoptive cell therapy
  • TIL tumor infiltrating lymphocyte
  • methods and materials provided herein can be used to treat a mammal (e.g., a human) having cancer (e.g., metastatic cancer) where the cancer treatment is selected based on whether or not the cancer is likely to be responsive to an ACT (e.g., a TIL therapy).
  • B ACKGROUND I NFORMATION ACTs have improved cancer
  • a TIL therapy can mediate metastatic tumor regression of multiple solid tumor types that have shown resistance to other cancer treatments such as immune checkpoint inhibitors.
  • patients must be subjected to a surgical harvest of tumor sample, and then wait about three weeks for the tumor sample to be tested for TIL growth and TIL tumor reactivity. This process of testing tumor samples is both time consuming and resource-intensive (see, e.g., Rosenberg et al., Science, 348(6230):62-8 (2015); and Chandran et al., Lancet Oncol., 18(6):792-802 (2017)).
  • This document provides methods and materials for assessing and/or treating a mammal (e.g., a human) having cancer (e.g., metastatic cancer).
  • cancer e.g., metastatic cancer
  • this document provides methods and materials for identifying whether or not a cancer (e.g., a Attorney Docket No.45059-0063P01 / 05801 / 06119 metastatic cancer) is likely to respond to an ACT such as a TIL therapy (e.g., by detecting the TILScore of the cancer).
  • ACT such as a TIL therapy
  • this document provides methods and materials for detecting the TILScore of a cancer (e.g., a metastatic cancer).
  • a TILScore can be detected in a sample (e.g., a tissue sample containing one or more cancer cells) from a mammal having cancer (e.g., metastatic cancer).
  • a sample obtained from a mammal having cancer e.g., metastatic cancer
  • an ACT e.g., a TIL therapy
  • nucleic acids listed in Table 1 that are differentially expressed in a distinct transcriptomic signature (e.g., a pan-cancer transcriptomic signature) that can be used to calculate a TILScore that can indicate whether or not the mammal (e.g., human) is likely to respond to an ACT (e.g., TIL therapy), regardless of the tumor location and regardless of the tumor origin.
  • a TILScore can indicate whether or not the mammal (e.g., human) is likely to respond to an ACT (e.g., TIL therapy)
  • ACT e.g., TIL therapy
  • a core-like tumor biopsy obtained from a mammal (e.g., a human) having cancer can be used to determine the TILScore of the cancer, thereby determining whether or not the cancer is likely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of a core-like biopsy obtained from a mammal (e.g., a human) having cancer can be calculated based on a relative rank 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.
  • a TILScore of at least 0.15 can indicate that the cancer is a cancer that is responsive to an ACT such as a TIL therapy.
  • ACT ACT
  • TILs can be obtained from that mammal and expanded ex vivo to create a culture of tumor reactive TILs that can be administered to that mammal to treat the mammal’s cancer.
  • a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • a TIL therapy e.g., a TIL therapy
  • the ability to determine whether or not a cancer is likely to respond to an ACT e.g., a TIL therapy
  • an ACT e.g., a TIL therapy
  • clinicians to provide a personalized approach in selecting cancer treatments, thereby improving disease-free survival and/or overall survival for this identified patient population.
  • the ability to determine whether or not a cancer is likely to respond to an ACT e.g., a TIL therapy
  • one aspect of this document features methods for identifying a mammal having cancer likely to respond to an ACT.
  • the methods can include, or consist essentially of, (a) determining that a sample obtained from a mammal and comprising cancer cells has a tumor infiltrating lymphocyte score (TILScore) of at least 0.15, where the TILScore is calculated based on a relative rank of at least 30 nucleic acids listed in Table 1; and (b) classifying the cancer as being likely to respond to the ACT.
  • the mammal can be a human.
  • the ACT can include a TIL therapy.
  • the cancer can include a solid tumor.
  • the at least 30 nucleic acids listed in Table 1 can be at least 50 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can be at least 100 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can include at least 80 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 90 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #50.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #40.
  • this document features methods for identifying a mammal having cancer unlikely to respond to an ACT.
  • the methods can include, or consist essentially of, (a) determining that a sample obtained from a mammal and comprising cancer cells has a TILScore of less than 0.15, where the TILScore is calculated based on a relative rank of a set of nucleic acids that comprises each of the 30 nucleic acids listed in Table 1 as rank #1 to Attorney Docket No.45059-0063P01 / 05801 / 06119 rank #30; and (b) classifying the cancer as being unlikely to respond to the ACT.
  • the mammal can be a human.
  • the ACT can include a TIL therapy.
  • the cancer can include a solid tumor.
  • this document features methods for selecting a treatment for a mammal having cancer.
  • the methods can include, or consist essentially of, (a) determining that a sample obtained from a mammal having cancer and comprising cancer cells has a TILScore of at least 0.15, where the TILScore is calculated based on a relative rank of at least 30 nucleic acids listed in Table 1; and (b) selecting an ACT as a treatment of cancer for the mammal.
  • the mammal can be a human.
  • the ACT can include a TIL therapy.
  • the cancer can include a solid tumor.
  • the at least 30 nucleic acids listed in Table 1 can be at least 50 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can be at least 100 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can include at least 80 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 90 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #50.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #40.
  • this document features methods for selecting a treatment for a mammal having cancer.
  • the methods can include, or consist essentially of, (a) determining that a sample obtained from a mammal having cancer and including cancer cells has a TILScore of less than 0.15, where the TILScore is calculated based on a relative rank of a set of nucleic acids that comprises each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30; and (b) selecting a cancer treatment other than an ACT for the mammal.
  • the mammal can be a human.
  • the ACT can include a TIL therapy.
  • the cancer can include a solid tumor.
  • the cancer treatment can include radiation therapy.
  • the cancer treatment can include administering an anti-cancer agent selected from the group consisting of a chemotherapy, a targeted therapy, and an angiogenesis inhibitor.
  • this document features methods for preparing a treatment for a mammal having cancer.
  • the methods can include, or consist essentially of, (a) determining Attorney Docket No.45059-0063P01 / 05801 / 06119 that a sample obtained from the mammal and comprising cancer cells has a TILScore of at least 0.15, where the TILScore is calculated based on a relative rank of at least 30 nucleic acids listed in Table 1; and (b) expanding TILs obtained from the mammal ex vivo to obtain expanded TILs for administration to the mammal.
  • the mammal can be a human.
  • the cancer can include a solid tumor.
  • the at least 30 nucleic acids listed in Table 1 can be at least 50 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can be at least 100 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can include at least 80 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 90 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #50.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #40.
  • the method also can include administering at least a portion of the expanded TILs to the mammal.
  • this document features methods for preparing a cancer treatment.
  • the methods can include, or consist essentially of, expanding TILs obtained from a mammal identified as having a TILScore of at least 0.15 to form a cell population for administration to the mammal to treat cancer, where the TILScore is calculated based on a relative rank of at least 30 nucleic acids listed in Table 1.
  • the mammal can be a human.
  • the cancer can include a solid tumor.
  • the at least 30 nucleic acids listed in Table 1 can be at least 50 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can be at least 100 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can include at least 80 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 90 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #50.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #40.
  • the method also can include administering at least a portion of the cell population to the mammal.
  • this document features methods for treating a mammal having cancer.
  • the methods can include, or consist essentially of, (a) determining that a sample obtained from the mammal and comprising cancer cells has a TILScore of at least 0.15, where the TILScore is calculated based on a relative rank of at least 30 nucleic acids listed in Table 1; and (b) administering an ACT to the mammal.
  • the mammal can be a human.
  • the ACT can include a TIL therapy.
  • the cancer can include a solid tumor.
  • the at least 30 nucleic acids listed in Table 1 can be at least 50 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can be at least 100 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can include at least 80 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 90 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #50.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #40.
  • this document features methods for treating cancer.
  • the methods can include, or consist essentially of, administering an ACT to a mammal identified as having a TILScore of at least 0.15, where the TILScore is determined from a sample obtained from the mammal and comprising cancer cells, and where the TILScore is calculated based on a relative rank of at least 30 nucleic acids listed in Table 1.
  • the mammal can be a human.
  • the ACT can include a TIL therapy.
  • the cancer can include a solid tumor.
  • the at least 30 nucleic acids listed in Table 1 can be at least 50 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can be at least 100 nucleic acids listed in Table 1.
  • the at least 30 nucleic acids listed in Table 1 can include at least 80 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 90 percent of nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #50.
  • the at least 30 nucleic acids listed in Table 1 can include at least 30 nucleic acids listed in Table 1 as having rank #1 to rank #40.
  • this document features methods for treating a mammal having cancer.
  • the methods can include, or consist essentially of, (a) determining that a sample Attorney Docket No.45059-0063P01 / 05801 / 06119 obtained from the mammal and comprising cancer cells has a TILScore of less than 0.15, where the TILScore is calculated based on a relative rank of a set of nucleic acids that comprises each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30; and (b) administering a cancer treatment other than an ACT to the mammal.
  • the mammal can be a human.
  • the ACT can include a TIL therapy.
  • the cancer can include a solid tumor.
  • the cancer treatment can include performing surgery.
  • the cancer treatment can include radiation therapy.
  • the cancer treatment can include administering an anti-cancer agent selected from the group consisting of a chemotherapy, a targeted therapy, and an angiogenesis inhibitor.
  • this document features methods for treating cancer.
  • the methods can include, or consist essentially of, administering a cancer treatment other than an ACT to a mammal identified as having cancer cells having a TILScore of less than 0.15, where the TILScore is calculated based on a relative rank of a set of nucleic acids that comprises each of the 30 nucleic acids listed in Table 1 as rank #1 to rank #30.
  • the mammal can be a human.
  • the ACT can include a TIL therapy.
  • the cancer can include a solid tumor.
  • the cancer treatment can include performing surgery.
  • the cancer treatment can include radiation therapy.
  • the cancer treatment can include administering an anti-cancer agent selected from the group consisting of a chemotherapy, a targeted therapy, and an angiogenesis inhibitor.
  • an anti-cancer agent selected from the group consisting of a chemotherapy, a targeted therapy, and an angiogenesis inhibitor.
  • FIG. 1 A schematic showing steps and times involved to perform current methods in practice for screening a tumor tissue for TIL reactivity (left side) as compared to steps and times involved to screen a tumor tissue using an exemplary method of one embodiment provided herein (right side).
  • Figure 2. A schematic showing TILScore development.
  • PC principal components
  • Figure 5 A heatmap of principal components (PC) correlations with hallmark genesets along with functional annotation of clusters (A, B, C, D).
  • Figure 5. Identification of PC2 relationship with Cluster B.
  • Figure 6. Gene types in PC2-immune axis gene list.
  • Figure 7. Functional annotation of genes in PC2-immune axis gene list.
  • Figure 8. Pie charts of tumor histologies in validation and test cohorts.
  • Figure 9. TILScore predictive ability in training, validation, and test cohorts.
  • Figure 10. TILScore predicted TIL reactivity in the combined pan-cancer cohort.
  • the graphs display candidate gene set enrichment scores using singscores (x-axis) versus % tumor reactive TIL cultures (y-axis) generated from 194 individual metastases.
  • Figure 13 Example of TILScore predicting TIL reactivity and response to TIL therapy in a patient with refractory metastatic peritoneal mesothelioma. Attorney Docket No.45059-0063P01 / 05801 / 06119 Figure 14.
  • This document provides methods and materials for assessing and/or treating a mammal (e.g., a human) having cancer (e.g., metastatic cancer). For example, this document provides methods and materials for identifying whether or not a cancer (e.g., a metastatic cancer) is likely to respond to an ACT such as a TIL therapy (e.g., by determining the TILScore of the cancer), and, optionally, treating the mammal. In some cases, the methods and materials described herein can be used to predict responsiveness to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a sample e.g., a tissue sample containing one or more cancer cells
  • a mammal having cancer e.g., metastatic cancer
  • an ACT e.g., a TIL therapy
  • TILs can be obtained from that mammal and expanded ex vivo to create a culture of tumor reactive TILs that can be administered to that mammal to treat the mammal’s cancer.
  • a biopsy that includes cancer cells can be obtained from a mammal (e.g., a human) having cancer and can be assessed to determine if the cancer cells have a TILScore that indicates that the mammal’s cancer is likely to respond to an ACT (e.g., a TIL therapy) as described herein. If the TILScore of the cancer cells indicates that the mammal’s cancer is likely to respond to an ACT (e.g., a TIL therapy), then TILs obtained from that mammal can be expanded ex vivo to create a culture of tumor reactive TILs. Once those tumor reactive TILs are obtained, they can be administered to the mammal to treat the mammal’s cancer.
  • ACT e.g., a TIL therapy
  • TILs obtained from a mammal e.g., a human such as a human identified as having a cancer that is responsive to an ACT such as a TIL therapy as described herein
  • TILs can be expanded ex vivo by culturing the TILs in the presence of one or more polypeptides that can promote the growth Attorney Docket No.45059-0063P01 / 05801 / 06119 and/or differentiation of immune cells.
  • polypeptides that can promote the growth and/or differentiation of immune cells and that can be used to expand TILs ex vivo include, without limitation, interleukin (IL)-2, IL-7, IL-15, IL-21, and anti-CD3 polypeptides (e.g., anti-CD3 antibodies).
  • ILs can be expanded ex vivo by culturing the TILs in the presence of one or more IL-2 polypeptides and in the presence of one or more anti-CD3 antibodies.
  • TILs can be expanded ex vivo as described elsewhere (see, e.g., Chandran et al., Lancet Oncol., 18: 792-802 (2017) at, for example, page 794).
  • the methods and materials described herein can be used to predict responsiveness to an ACT (e.g., a TIL therapy) in less than about 2 weeks (e.g., less than about 1 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).
  • ACT e.g., a TIL therapy
  • a sample e.g., a tumor tissue sample
  • a mammal having cancer e.g., metastatic cancer
  • an ACT e.g., a TIL therapy
  • the cancer is likely to respond to an ACT (e.g., a TIL therapy) based, at least in part, on the TILScore of the cancer in from about 2 days to about 2 weeks (e.g., from about 2 days to about 1 week, from about 2 days to about 5 days, from about 5 days to about 2 weeks, from about 1 week to about 2 weeks, or from about 5 days to about 1 week).
  • a mammal e.g., a human having cancer (e.g., metastatic cancer) can be assessed to determine whether the cancer is likely to respond to an ACT (e.g., a TIL therapy) by detecting the TILScore of the cancer.
  • ACT e.g., a TIL therapy
  • a sample e.g., a tumor tissue sample obtained from a mammal having cancer can be assessed to determine if the mammal is likely to respond to an ACT (e.g., a TIL therapy) based, at least in part, on the TILScore of the cancer.
  • a TILScore of a sample obtained from a mammal having cancer can be calculated based on a relative rank 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.
  • a TILScore for a tumor tissue sample is calculated using 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 as follows. First, the nucleic acids are ranked based on their transcript abundance in increasing Attorney Docket No.45059-0063P01 / 05801 / 06119 order for the up-set.
  • a sample with a high score can be interpreted as having a transcriptome that is concordant to the specified signature, and scores reflect the relative mean percentile rank of the TILScore gene set within each sample.
  • the score (S) and normalized score (S) are defined as: where dir is the gene set direction (e.g., expected up- or down- regulated genes), S dir, i is the score for sample i against the directed gene set, R g dir,i is the rank of gene g in the directed gene set (e.g., with increasing transcript abundance for expected up-regulated genes and decreasing abundance for expected down-regulated genes), N dir, i is the number of genes in the expected up- or down-regulated gene set that are observed within the data (i.e., signature genes not present within the RNA abundance data are excluded), Sdir,i is the normalized score for sample i against genes in the signature, and S min, i and S max, i are the theoretical minimum and maximum mean ranks which can be derived from an arithmetic sum (e.g., assuming unique ranks).
  • dir is the gene set direction (e.g., expected up- or down- regulated genes)
  • S dir, i is the score for sample i against the directed gene set
  • Any appropriate mammal having cancer can be assessed, prepared for treatment, and/or treated as described herein.
  • mammals that can have cancer and can be assessed, prepared for treatment, and/or treated as described herein include, without limitation, humans, non-human primates (e.g., monkeys), dogs, cats, horses, cows, pigs, sheep, mice, and rats.
  • a human having cancer e.g., metastatic cancer
  • the cancer can be any type of cancer.
  • a cancer assessed and/or treated as described herein can include one or more solid tumors.
  • a cancer assessed and/or treated as described herein can be a blood cancer.
  • a cancer assessed and/or treated as described herein can be a primary cancer.
  • a cancer assessed and/or treated as described herein can be a metastatic cancer.
  • a cancer assessed and/or treated as described herein can be a refractory cancer. In some cases, a cancer assessed and/or treated as described herein can be a relapsed cancer.
  • cancers that can be assessed and/or treated as described herein include, without limitation, uveal melanomas, cutaneous melanomas, liver cancers, lung cancers, breast cancers, lymph cancers, pancreatic cancers (e.g., pancreatic adenocarcinomas), spleen cancers, biliary tract cancers, mesotheliomas (e.g., peritoneal mesotheliomas), Merkel cell carcinomas, sarcomas, gastric cancers (e.g., gastric adenocarcinomas), mucosal melanomas, squamous cell carcinomas, colorectal adenocarcinomas, ovarian carcinomas, gastrointestinal stromal tumors, merkel cell carcinomas, neuroendocrine tumor
  • a mammal having cancer and being assessed and/or prepared for treatment (and optionally treated) as described herein, can have multiple (e.g., two or more) different types of cancer.
  • a mammal e.g., a human having cancer and Attorney Docket No.45059-0063P01 / 05801 / 06119 being assessed and/or prepared for treatment (and optionally treated) as described herein, can have a cancer that has metastasized to one or more different locations.
  • the methods described herein can include identifying a mammal (e.g., a human) as having cancer (e.g., metastatic cancer).
  • a TILScore used to determine whether or not a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • a relative rank 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
  • a TILScore of a sample obtained from a mammal having cancer can be calculated based on a relative rank 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 to determine whether or not the cancer is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer calculated based on a relative rank 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 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 that mammal can be identified as having cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • an ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer calculated based on a relative rank of at least 30 of the nucleic acids listed in Table 1 is less than 0.15
  • that mammal can be identified as having cancer that is unlikely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer calculated based on a relative rank of the 30 nucleic acids listed in Table 1 as having rank #1 to rank #30 that is at least 0.15 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer Attorney Docket No.45059-0063P01 / 05801 / 06119 cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 74 nucleic acids listed in Table 1 as having rank #1 to rank #74 that is at least 0.15 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • an ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 31 nucleic acids listed in Table 1 as having rank #1 to rank #31 that is at least 0.15 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy)
  • a TILScore of cancer cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 32 nucleic acids listed in Table 1 as having rank #1 to rank #32 that is at least 0.15 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy), and so forth up to rank #74.
  • a TILScore is not at least 0.15 in the examples of this paragraph, then the mammal can be identified as having cancer that is unlikely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 75 nucleic acids listed in Table 1 as having rank #1 to rank #75 that is at least 0.16 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer calculated based on a relative rank of the 89 nucleic acids listed in Table 1 as having rank #1 to rank #89 that is at least 0.16 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 76 nucleic acids listed in Table 1 as having rank #1 to rank #76 that is at least 0.16 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy)
  • a TILScore of cancer cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 77 nucleic acids listed in Table 1 as having rank #1 to rank #77 that is at least 0.16 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy), and so forth up to rank #89.
  • a TILScore is not at least 0.16 in the examples of this paragraph, then the mammal can be identified as having cancer that is unlikely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal e.g., a human
  • a TILScore of cancer cells obtained from a mammal having cancer calculated based on a relative rank of the 90 nucleic acids listed in Table 1 as having rank #1 to rank #90 that is at least 0.17 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer calculated based on a relative rank of the 95 nucleic acids listed in Table 1 as having rank #1 to rank #95 that is at least 0.17 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 91 nucleic acids listed in Table 1 as having rank #1 to rank #91 that is at least 0.17 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy)
  • a TILScore of cancer cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 92 nucleic acids listed in Table 1 as having rank #1 to rank #92 that is at least 0.17 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy), and so forth up to rank #95.
  • a TILScore is not at least 0.17 in the examples of this paragraph, then the mammal can be identified as having cancer that is unlikely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 96 nucleic acids listed in Table 1 as having rank #1 to rank #96 that is at least 0.18 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer calculated based on a relative rank of the 135 nucleic acids listed in Table 1 as having rank #1 to rank #135 that is at least 0.18 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal having cancer calculated based on a relative rank of the 97 nucleic acids listed in Table 1 as having rank #1 to rank #97 that is at least 0.18 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy)
  • a TILScore of cancer cells obtained from a mammal having cancer calculated based on a relative rank of the 98 nucleic acids listed in Table 1 as having rank #1 to rank #98 that is at least 0.18
  • the Attorney Docket No.45059-0063P01 / 05801 / 06119 mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy), and so forth up to rank #135.
  • a TILScore is not at least 0.18 in the examples of this paragraph, then the mammal can be identified as having cancer that is unlikely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 136 nucleic acids listed in Table 1 as having rank #1 to rank #136 that is at least 0.19 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer calculated based on a relative rank of the 186 nucleic acids listed in Table 1 as having rank #1 to rank #186 that is at least 0.19 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal having cancer calculated based on a relative rank of the 137 nucleic acids listed in Table 1 as having rank #1 to rank #137 that is at least 0.19 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy)
  • a TILScore of cancer cells obtained from a mammal having cancer calculated based on a relative rank of the 138 nucleic acids listed in Table 1 as having rank #1 to rank #138 that is at least 0.19 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy), and so forth up to rank #186.
  • a TILScore is not at least 0.19 in the examples of this paragraph, then the mammal can be identified as having cancer that is unlikely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer cells obtained from a mammal (e.g., a human) having cancer calculated based on a relative rank of the 187 nucleic acids listed in Table 1 as having rank #1 to rank #187 that is at least 0.2 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer calculated based on a relative rank of the 265 nucleic acids listed in Table 1 as having rank #1 to rank #265 that is at least 0.2 can indicate that the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal having cancer calculated based on a relative rank of the 188 nucleic acids listed in Table 1 as Attorney Docket No.45059-0063P01 / 05801 / 06119 having rank #1 to rank #188 that is at least 0.2
  • a TILScore of cancer cells obtained from a mammal having cancer calculated based on a relative rank of the 189 nucleic acids listed in Table 1 as having rank #1 to rank #189 that is at least 0.2
  • the mammal has a cancer that is likely to respond to an ACT (e.g., a TIL therapy), and so forth up to rank #265.
  • a TILScore used to determine whether or not a cancer (e.g., a metastatic cancer) is likely to respond to an ACT (e.g., a TIL therapy) can be calculated based on a relative rank of at least 30 percent (e.g., at least 40 percent, at least 50 percent, at least percent, least 70 percent, least 80 percent, or least 90 percent) of the nucleic acids ranked as #1 to #30 in Table 1.
  • TILScore of a sample e.g., a tumor tissue sample obtained from a mammal having cancer can be calculated based on a relative rank of at least 30 percent (e.g., at least 40 percent, at least 50 percent, at least 60 percent, least 70 percent, least 80 percent, or least 90 percent) of the nucleic acids ranked as #1 to #30 in Table 1 to determine whether or not the cancer is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • cancer cells obtained from a mammal e.g., a human having cancer are determined to have a TILScore 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), then that mammal can be identified as having cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • cancer cells obtained from a mammal e.g., a human
  • a mammal e.g., a human
  • that mammal can be identified as having cancer that is unlikely to respond to an ACT (e.g., a TIL therapy).
  • a TILScore used to determine whether or not a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • a TILScore used to determine whether or not a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • a TILScore of a sample e.g., a tumor tissue sample obtained from a mammal having cancer can be calculated based on a relative rank of each of the nucleic acids ranked as #1 to #30 in Table 1 to determine whether or not the cancer is likely to respond to an ACT (e.g., a TIL therapy).
  • an ACT e.g., a TIL therapy
  • cancer cells obtained from a mammal e.g., a human having cancer are determined to have a TILScore 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), then that mammal can be identified as having cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore used to determine whether or not a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • 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 of the nucleic acids ranked as #1 to #30 in Table 1.
  • a TILScore of a sample obtained from a mammal having cancer 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) of the nucleic acids ranked as #1 to #30 in Table 1 to determine whether or not the cancer is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer 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) of the nucleic acids ranked as #1 to #30 in Table 1 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 that mammal can be identified as having cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • an ACT e.g., a TIL therapy
  • a TILScore used to determine whether or not a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • a relative rank of at least 50 percent e.g., at least 60 percent, least 70 percent, least 80 percent, or least 90 percent
  • a TILScore of a sample obtained from a mammal having cancer can be calculated based on a relative rank of at least 50 percent (e.g., at least 60 percent, least 70 percent, least 80 percent, or least 90 percent) of the nucleic acids ranked as #1 to #60 in Table 1 to determine whether or not the cancer is likely to respond to an ACT (e.g., a TIL therapy).
  • an ACT e.g., a TIL therapy
  • cancer cells obtained from a mammal e.g., a human having cancer are determined to have a TILScore of at least 0.15 (e.g., at least 0.15, at least 0.16, at Attorney Docket No.45059-0063P01 / 05801 / 06119 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 that mammal can be identified as having cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer calculated based on a relative rank of at least 40 percent (e.g., at least 50 percent, at least 60 percent, least 70 percent, least 80 percent, or least 90 percent) of the nucleic acids ranked as #1 to #30 in Table 1 and at least 60 percent (e.g., least 70 percent, least 80 percent, or least 90 percent) of the nucleic acids ranked as #31 to #60 in Table 1 is at least than 0.15, then that mammal can be identified as having cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • an ACT e.g., a TIL therapy
  • a TILScore used to determine whether or not a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • a relative rank of at least 33.3 percent e.g., at least 40 percent, at least 50 percent, at least 60 percent, least 70 percent, least 80 percent, or least 90 percent
  • a TILScore of a sample obtained from a mammal having cancer can be calculated based on a relative rank of at least 33.3 percent (e.g., at least 40 percent, at least 50 percent, at least 60 percent, least 70 percent, least 80 percent, or least 90 percent) of the nucleic acids ranked as #1 to #90 in Table 1 to determine whether or not the cancer is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • cancer cells obtained from a mammal e.g., a human having cancer are determined to have a TILScore 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), then that mammal can be identified as having cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore used to determine whether or not a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • 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
  • 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
  • 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
  • at least 3 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,
  • a TILScore of a sample obtained from a mammal having cancer 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) of the nucleic acids ranked as #1 to #30 in Table 1 and at least 21 (e.g., at least 22, 23, 24, 25, 26, 27, 28, 29, or 30) of the nucleic acids ranked as #31 to #265 in Table 1 to determine whether or not the cancer is likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer 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) of the nucleic acids ranked as #1 to #30 in Table 1 and at least 21 (e.g., at least 22, 23, 24, 25, 26, 27, 28, 29, or 30) of the nucleic acids ranked as #31 to #265 in Table 1 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 that mammal can be identified as having cancer that is likely to respond to an ACT (e.g., a TIL therapy).
  • an ACT e.g., a TIL therapy
  • a TILScore used to determine whether or not a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • 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
  • 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
  • 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
  • at least 12 e.g., at least 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30
  • a TILScore of a sample obtained from a mammal having cancer 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) of the nucleic acids ranked as #1 to #30 in Table 1, 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 the nucleic acids ranked as #31 to #60 in Table 1, and at least 12 (e.g., at least 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of the nucleic acids ranked as #61 to #265 in Table 1 to determine whether or not the cancer is likely to respond to an ACT (e.g., a TIL therapy).
  • an ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer 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) of the nucleic acids ranked as #1 to #30 in Table 1
  • 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
  • at least 12 e.g., at least 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30
  • at least 0.15 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
  • a TILScore used to determine whether or not a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • 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
  • 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
  • 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
  • at least 3 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,
  • a TILScore of a sample obtained from a mammal having cancer 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) of the nucleic acids ranked as #1 to #30 in Table 1, 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 the nucleic acids ranked as #31 to #60 in Table 1, 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 the nucleic acids ranked as #61 to #90 in Table 1, and at least 3 (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) of the nucleic acids ranked as #91 to #265
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer 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) of the nucleic acids ranked as #1 to #30 in Table 1
  • 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
  • the nucleic acids ranked as #31 to #60 in Table 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 the nucleic acids ranked as #61 to #90 in Table 1
  • at least 3 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
  • a TILScore used to determine whether or not a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • a relative rank of at least 30 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) of the nucleic acids ranked as #1 to #265 in Table 1.
  • a TILScore of a sample obtained from a mammal having cancer can be calculated based on a relative rank of at least 30 (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, Attorney Docket No.45059-0063P01 / 05801 / 06119 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) of the nucleic acids ranked as #1 to #265 in Table 1 to determine whether or not the cancer is likely to respond to an ACT (e.g., a TIL therapy).
  • an ACT e.g., a TIL therapy
  • a TILScore of cancer cells obtained from a mammal e.g., a human having cancer calculated based on a relative rank of at least 30 (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) of the nucleic acids ranked as #1 to #265 in Table 1 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 that mammal can be
  • a sample can be a biological sample.
  • a sample can contain one or more cancer cells.
  • a sample can contain one or more biological molecules (e.g., nucleic acids such as DNA and RNA, polypeptides, carbohydrates, lipids, hormones, and/or metabolites).
  • tissue samples such as tumor tissue samples (e.g., tumor fragments) and tumor single cell suspensions.
  • a sample can be a fresh sample (e.g., a fresh frozen sample).
  • one or more biological molecules can be isolated from a sample (e.g., from one or more cancer cells within the sample).
  • nucleic acid can be isolated from a sample and can be assessed as described herein. Any appropriate method can be used to obtain a sample (e.g., a tumor tissue sample) from a mammal (e.g., a human) having cancer (e.g., metastatic cancer).
  • a sample can be obtained using a core biopsy or a core-like biopsy.
  • a sample e.g., a tumor tissue sample
  • a mammal e.g., a human
  • cancer e.g., metastatic cancer
  • a TILScore of a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • a Attorney Docket No.45059-0063P01 / 05801 / 06119 TILScore 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
  • a sample e.g., a tumor tissue sample
  • a mammal e.g., a human
  • cancer e.g., metastatic cancer
  • a TILScore of a cancer can be used to identify the cancer as not being likely to respond to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • a TILScore of less than 0.15 in a sample e.g., a tumor tissue sample obtained from a mammal (e.g., a human) having cancer (e.g., metastatic cancer) can be used to identify the cancer as being unlikely to respond to an ACT (e.g., a TIL therapy).
  • a mammal e.g., a human having a cancer (e.g., a metastatic cancer) that is identified as being likely to respond to an ACT (e.g., a TIL therapy) as described herein (e.g., based, at least in part, on a TILScore of the cancer) can be selected to receive an ACT (e.g., a TIL therapy) to treat the cancer.
  • ACT e.g., a TIL therapy
  • a mammal having a cancer e.g., a metastatic cancer
  • a TILScore 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
  • an ACT e.g., a TIL therapy
  • a mammal e.g., a human having a cancer (e.g., a metastatic cancer) that is identified as not being likely to respond to an ACT (e.g., a TIL therapy) as described herein (e.g., based, at least in part, on a TILScore of the cancer) can be selected to receive an alternative cancer treatment (e.g., one or more cancer treatments that are not an ACT) to treat the cancer.
  • an alternative cancer treatment e.g., one or more cancer treatments that are not an ACT
  • a mammal e.g., a human having cancer (e.g., metastatic cancer).
  • a mammal e.g., a human having cancer and assessed as described herein (e.g., to determine whether or not the cancer is likely to respond to an ACT such as a TIL therapy based, at least in part, on a TILScore of the cancer) can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) cancer treatments, where the one or more cancer treatments are Attorney Docket No.45059-0063P01 / 05801 / 06119 effective to treat the cancer within the mammal.
  • a mammal having cancer can be administered or instructed to self-administer one or more cancer treatments selected based, at least in part, on whether or not the cancer is likely to respond to an ACT such as a TIL therapy (e.g., based, at least in part, on a TILScore of the cancer).
  • an ACT such as a TIL therapy
  • a mammal having a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • the mammal can be administered or instructed to self-administer an ACT.
  • a mammal having a cancer identified as having a TILScore 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) can be administered or instructed to self-administer one or more ACTs.
  • ACTs that can be administered to a mammal (e.g., a human) having a cancer (e.g., a metastatic cancer) identified has being likely to respond to an ACT as described herein include, without limitation, TIL therapies.
  • a mammal e.g., a human
  • a cancer e.g., a metastatic cancer
  • an ACT e.g., a TIL therapy
  • the mammal can be administered or instructed to self-administer one or more (e.g., one, two, three, four, five, or more) alternative cancer treatments (e.g., one or more cancer treatments that are not an ACT such as a TIL therapy).
  • a mammal having a cancer e.g., a metastatic cancer identified as having a TILScore of less than 0.15 can be administered or instructed to self- administer one or more alternative cancer treatments that are not an ACT (e.g., a TIL therapy).
  • alternative cancer treatments that are not an ACT include, without limitation, performing surgery, performing radiation therapies, and administering one or more anti-cancer agents (e.g., chemotherapies, administering targeted therapies (e.g., monoclonal antibody therapies), and administering angiogenesis inhibitors).
  • the treatment when treating a mammal (e.g., a human) having cancer (e.g., metastatic cancer) as described herein, the treatment can be effective to treat the cancer.
  • the number of cancer cells present within a mammal can be reduced using the methods and materials described herein.
  • the size (e.g., volume) of one or more Attorney Docket No.45059-0063P01 / 05801 / 06119 tumors present within a mammal can be reduced using the methods and materials described herein.
  • the methods and materials described herein can be used to reduce the size of one or more tumors present within a mammal having cancer (e.g., metastatic cancer) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.
  • the methods and materials described herein can be used to treat cancer in a manner such that the size (e.g., volume) of one or more tumors present within a mammal does not increase.
  • the treatment when treating a mammal (e.g., a human) having cancer (e.g., metastatic cancer) as described herein, the treatment can be effective to improve survival of the mammal.
  • the methods and materials described herein can be used to improve disease-free survival (e.g., relapse-free survival).
  • the methods and materials described herein can be used to improve progression-free survival.
  • the methods and materials described herein can be used to improve the survival of a mammal having cancer (e.g., metastatic cancer) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.
  • TIL Transcriptomic-Guided Tumor Infiltrating Lymphocyte
  • TIL Transcriptomic-Guided Tumor Infiltrating Lymphocyte
  • TILScore The methodology used to identify nucleic acids and generate a TILScore is shown generally in Figure 2.
  • Uveal melanoma metastases are poorly immunogenic cancers.100 uveal melanoma metastases were surgically resected from 84 patients, with 12 patients undergoing multiple tumor harvests. The locations of the harvested metastases are shown in Figure 3.
  • the median age of the patients was 56 years, with 52% of the patients being female and 48% of the patients being male.
  • the median tumor mutation burden (TMB) was 0.64 mutations/Megabase.46/84 of the patients were subjected to previous checkpoint blockade.
  • Clusters C and D were not found to independently correlate with any of the three PCs ( Figure 5).
  • To interrogate PC2 the PC of interest given its unique correlation with immune gene sets, gene loadings for PC2 were interrogated, and contributions of genes to positive or negative aspects of PC3 were identified.2394 genes of interest were identified that correlated with PC2 in the same direction as hallmark immune genesets. Gene type and functional annotation showed coding and noncoding genes ( Figure 6) and immune-related functions ( Figure 7).
  • TPM transcripts per million
  • Validation and Application of TILScore Multihistology Analysis To determine whether the genelist of 2394 can predict TIL reactivity in other poorly immunogenic solid tumors, 94 samples of multiple different solid tumor types were obtained ( Figure 8). Immunologic studies and RNAseq plus TILScore were applied to these samples. Genes were ranked by strength of correlation with immunologic TIL reactivity in the training (100 uveal melanoma) cohort.
  • the list of 2394 was then sequentially shaved from weakest correlated gene to strongest and each gene set tested for ability to predict TIL reactivity in the training and validation cohorts.
  • the geneset of 265 (Table 1) was selected based upon its combined strongest predictive value in the validation cohort and named TILScore.
  • TILScore correlated with and successfully classified TIL reactivity in the training, validation, and independent test cohorts ( Figure 9).
  • a pan-cancer cohort was generated by combining the metastatic uveal melanoma samples and the multihistology samples ( Figure 10), and TILScore analysis was run. The TILScore correlated with and successfully classified TIL reactivity in the combined pan-cancer cohort ( Figure 10).
  • TILScore reactivity probability calculator was generated using the following formula: where P is probability, e is Euler’s number, Bo is -4.514455, and B1x is 16.637663. Different thresholds for 25% probability of generating ?10% tumor reactive TIL cultures were calculated based on different numbers of gene sets used (including the selected TILScore of 265) ( Figure 11).
  • RNAseq and TILScore was applied to uveal melanoma samples obtained from 42 patients undergoing TIL therapy.
  • TILScore predicted RECIST response in these patients undergoing TIL therapy ( Figure 12).
  • TILScore Predicts TIL Reactivity in Poorly Immunogenic Cancers
  • TILScores were calculated in from a sample from a refractory Attorney Docket No.45059-0063P01 / 05801 / 06119 peritoneal mesothelioma patient, a 60-year-old female with metastatic malignant peritoneal mesothelioma.
  • the patient was previously treated with: 1) pemetrexed and cisplatin, 2) CRS/HIPEC with mitomycin-C (adjuvant pemetrexed and carboplatin), 3) right thoracotomy, debulking of right chest (adjuvant pemetrexed and carboplatin), 4) radiotherapy (5000 cGy to paraesophageal nodes), 5) palliative small bowel bypass with end colostomy, 6) anti-PD-1 therapy, and/or 7) anti-CTLA-4 plus anti-PD-1 therapy, and the patient experienced recurrence or progression on all these therapies.
  • the TILScore was found to be 0.297, and the probability of TIL reactivity was found to be 60.7% for this patient.
  • the TILScore predicted TIL reactivity and ACT response (Figure 13) in this patient with refractory peritoneal mesothelioma.
  • Example 2 Top 265 nucleic acids used to generate a TILScore. Nucleic acids were ranked in an order of contribution to effectively determining whether or not a cancer is likely to be responsive to an ACT such as a TIL therapy (Table 1). Table 1.
  • the success:futility cutoff was defined as the ability to generate ⁇ 10% tumor reactive TIL cultures from a single metastasis per the gold standard laboratory assay.
  • the graphs in Figure 11 display candidate gene set enrichment scores using singscores (x-axis) versus % tumor reactive TIL cultures (y-axis) generated from 194 individual metastases.
  • Dashed lines and values in Figure 11 represent success:futility cutoffs overlaid onto the total cohort of 194 individual metastases.
  • a tumor tissue sample is obtained from a human having cancer (e.g., metastatic cancer). The obtained sample is assessed to calculate a TILScore of the sample based on a relative rank of at least 80 percent (e.g., at least 90 percent, or 100 percent) of the 30 nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • the cancer is classified as being responsive to an ACT (e.g., a TIL therapy). If the sample has a TILScore of less than 0.15, then the cancer can be classified as not being responsive to an ACT (e.g., a TIL therapy).
  • ACT e.g., a TIL therapy
  • Example 6 Preparing a treatment for a human having cancer A tumor tissue sample is obtained from a human having cancer (e.g., metastatic cancer).
  • the obtained sample is assessed to calculate a TILScore of the sample based on a relative rank of at least 80 percent (e.g., at least 90 percent, or 100 percent) of the 30 nucleic acids listed in Table 1 as having rank #1 to rank #30. If the sample has a TILScore 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), then TILs obtained from that human are expanded ex vivo. Once expanded, the TILs are formulated into a composition for administration to the human to treat the human’s cancer.
  • a TILScore of the sample based on a relative rank of at least 80 percent (e.g., at least 90 percent, or 100 percent) of the 30 nucleic acids listed in Table 1 as having rank #1 to rank #30. If the sample has a TILScore of at least 0.15 (e.g
  • Example 7 Treating cancer A tumor tissue sample is obtained from a human having cancer (e.g., metastatic cancer). The obtained sample is assessed to calculate a TILScore of the sample based on a relative rank of at least 80 percent (e.g., at least 90 percent, or 100 percent) of the 30 nucleic acids listed in Table 1 as having rank #1 to rank #30.
  • TILs obtained from that human are expanded ex vivo. Once expanded, the TILs are formulated into a composition for administration to the human to treat the human’s cancer, and the formulated composition is administered to the human. Once administered to the human, the TILs can reduce the number of cancer cells present in the human.
  • Example 8 Treating cancer A tumor tissue sample is obtained from a human having cancer (e.g., metastatic cancer). The obtained sample is assessed to calculate a TILScore of the sample based on a relative rank of at least 80 percent (e.g., at least 90 percent, or 100 percent) of the 30 nucleic acids listed in Table 1 as having rank #1 to rank #30. If the sample has a TILScore of less than 0.15, then the human can be administered one or more (e.g., one, two, three, four, five, or more) alternative cancer treatments (e.g., one or more cancer treatments that are not an ACT such as a TIL therapy). The alternative cancer treatment can reduce the number of cancer cells present in the human.
  • a human having cancer e.g., metastatic cancer.
  • the alternative cancer treatment can reduce the number of cancer cells present in the human.

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