Abstract: A method of expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs may include the steps of: (a) obtaining and/or receiving a first population of TILs from surgical resection, needle biopsy, core biopsy, small biopsy, or other means for obtaining a sample that contains a mixture of tumor and TIL cells from a cancer in the subject or patient; performing an initial expansion (or priming first expansion) of the first population of TILs in the first cell culture medium to obtain a second population of TILs, wherein the first cell culture medium comprises IL-2, optionally OKT-3 (anti-CD3 antibody), and optionally antigen presenting cells (APCs), performing a rapid second expansion of the second population of TILs in a second cell culture medium to obtain a third population of TILs; wherein the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), and APCs; harvesting the third population of TILs; and genetically modifying TILs at any time prior to step (d) or after st

Abstract: Provided herein are compositions and methods for the treatment of cancers using modified TILs, wherein the modified TILs include one or more immunomodulatory agents (e.g., cytokines) associated with their cell surface. The immunomodulatory agents associated with the TILs provide a localized immunostimulatory effect that can advantageously enhance TIL survival, proliferation and/or anti-tumor activity in a patient recipient. As such, the compositions and methods disclosed herein provide effective cancer therapies.

Abstract: Provided herein are compositions and methods for the treatment of cancers using modified TILs, wherein the modified TILs include one or more immunomodulatory agents (e.g., cytokines) associated with their cell surface. The immunomodulatory agents associated with the TILs provide a localized immunostimulatory effect that can advantageously enhance TIL survival, proliferation and/or anti-tumor activity in a patient recipient. As such, the compositions and methods disclosed herein provide effective cancer therapies.

Abstract: Provided herein are compositions and methods for the treatment of cancers using modified TILs, wherein the modified TILs include one or more immunomodulatory agents (e.g., cytokines) associated with their cell surface. The immunomodulatory agents associated with the TILs provide a localized immunostimulatory effect that can advantageously enhance TIL survival, proliferation and/or anti-tumor activity in a patient recipient. As such, the compositions and methods disclosed herein provide effective cancer therapies.

Abstract: Provided herein are methods of producing TILs via (i) pre-REP stimulation with a combination of interferon gamma (IFN?) and an anti-PD-1 antibody, with or without a CD40 agonist, and with or without an anti-CTLA-4 antibody (ii) various concentrations of IL-15 and IL-21, with or without low-concentration IL-2, with or without an AKT inhibitor (AKTi) during REP expansion and/or pre-REP expansion, (iii) low-concentration IL-2 and an AKTi during REP expansion and/or pre-REP expansion, (iv) the combination of (i) and (ii), or (v) the combination of (i) and (iii).

Abstract: Provided herein are compositions and methods for the treatment of cancers using modified TILs, wherein the modified TILs include one or more immunomodulatory agents (e.g. cytokines) associated with their cell surface. The immunomodulatory agents associated with the TILs provide a localized immunostimulatory effect that can advantageously enhance TIL survival, proliferation and/or anti-tumor activity in a patient recipient. As such, the compositions and methods disclosed herein provide effective cancer therapies.

Abstract: Provided herein are TILs that are (i) CD39LO/CD69LO and/or CD39/CD69 double negative, (ii) CD39/CD69 double knock-out, or (iii) the combination of (i) and (ii). In some embodiments, the subject TILs are produced by genetically manipulating a population of TILs that have been selected for (i) CD39LO/CD69LO and/or CD39/CD69 double negative, (ii) CD39/CD69 double knock-out, or (iii) the combination of (i) and (ii) expression (e.g, a (i) CD39LO/CD69LO and/or CD39/CD69 double negative, (ii) CD39/CD69 double knock-out, or (iii) the combination of (i) and (ii) enriched TIL population). Also provided herein are expansion methods for producing such genetically modified TILs and methods of treatment using such TILs.

Abstract: Provided herein are methods of producing TILs via (i) pre-REP stimulation with a combination of interferon gamma (IFN?) and an anti-PD-1 antibody, with or without a CD40 agonist, and with or without an anti-CTLA-4 antibody (ii) various concentrations of IL-15 and IL-21, with or without low-concentration IL-2, with or without an AKT inhibitor (AKTi) during REP expansion and/or pre-REP expansion, (iii) low-concentration IL-2 and an AKTi during REP expansion and/or pre-REP expansion, (iv) the combination of (i) and (ii), or (v) the combination of (i) and (iii).

Abstract: The invention provides methods for identifying an individuals with a disease or disorder who is less likely to respond to immunotherapy alone, the method comprising determining the presence of a stromal gene signature in a sample from the individual, said signature comprising one or more of FAP, FN1, MMP2, PDGFRB, or THY, wherein an increase in the level of expression of the one or more genes in the stroma gene signature relative to a median level identifies an individual for treatment with an immunotherapy and with a suppressive stromal antagonist. In some aspects, the invention provides methods for treating an individual displaying the stromal gene signature. In other aspects, the invention provides kits for determining the presence of a stroma gene signature in a sample from an individual.

Abstract: The invention provides methods for identifying an individuals with a disease or disorder who is less likely to respond to immunotherapy alone, the method comprising determining the presence of a stromal gene signature in a sample from the individual, said signature comprising one or more of FAP, FN1, MMP2, PDGFRB, or THY, wherein an increase in the level of expression of the one or more genes in the stroma gene signature relative to a median level identifies an individual for treatment with an immunotherapy and with a suppressive stromal antagonist. In some aspects, the invention provides methods for treating an individual displaying the stromal gene signature. In other aspects, the invention provides kits for determining the presence of a stroma gene signature in a sample from an individual.