Tumor infiltrating lymphocytes and methods of therapy

Abstract

Genetically modified compositions, such as non-viral vectors and tumor infiltrating lymphocytes, for the treatment of gastrointestinal cancer are disclosed. Disclosed are methods of utilizing a CRISPR system to generate genetically modified compositions. Also disclosed are the methods of making and using the genetically modified compositions for the treatment of gastrointestinal cancer.

1 - 193 . (canceled) 
     
     
         194 . A therapeutic product that comprises a dosage form of a plurality of tumor infiltrating lymphocytes (TILs), wherein said TILs comprise a disruption a cytokine inducible SH2-containing protein (CISH) gene that suppresses expression of a CISH protein encoded by said CISH gene; and wherein said plurality of T cells express a T cell receptor (TCR) that specifically binds to a neoantigen; and wherein said plurality of TILs comprises CD4+ T cells and CD8+ T cells. 
     
     
         195 . The therapeutic product of  claim 194 , wherein said disruption is in exon 2 or exon 3 of said CISH gene. 
     
     
         196 . The therapeutic product of  claim 194 , wherein said disruption is in exon 3 of said CISH gene. 
     
     
         197 . The therapeutic product of  claim 194 , wherein said plurality of TILs comprises from about 1×10 9  to 1×10 11 , TILs, 3×10 9  to 1×10 11  TILs, 1×10 10  to 1×10 11  TILs, or 3×10 10  to 1×10 11  TILs. 
     
     
         198 . The therapeutic product of  claim 194 , wherein said plurality of TILs comprises from about 1×10 9  to 1×10 11  TILs. 
     
     
         199 . The therapeutic product of  claim 194 , further comprising a dosage form of an anti-fungal agent. 
     
     
         200 . The therapeutic product of  claim 199 , wherein said anti-fungal agent is an azole, polyene, allylamine, or echinocandin. 
     
     
         201 . The therapeutic product of  claim 199 , wherein said anti-fungal agent is an azole selected from the group consisting of fluconazole, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, and voriconazole. 
     
     
         202 . The therapeutic product of  claim 201 , wherein said anti-fungal agent comprises fuconazole. 
     
     
         203 . The therapeutic product of  claim 194 , further comprising a dosage form of a preparative regimen that comprises at least one immunosuppressant. 
     
     
         204 . The therapeutic product of  claim 203 , wherein said at least one immunosuppressant comprises cyclophosphamide, fludarabine, mechlorethamine, chlorambucil, melphalan, ifosfamide, thiotepa, hexamethylmelamine, busulfan, nitrosourea, methotrexate, azathioprine, mercaptopurine, procarbazine, dacarbazine, temozolomide, carmustine, lomustine, streptozocin, fluorouracil, dactinomycin, anthracycline, mitomycin C, bleomycin, mithramycin, mycophenolate mofetil, rapamycin, cyclosporin, deoxyspergualin, compstatin, methylprednisolone, leflunomide, abatacept, belatacept, sirolimus, everolimus, tacrolimus, daclizumab, basiliximab, infliximab, eculizumab, rituximab, alemtuzumab, tocilizumab, sarilumab, or olokizumab. 
     
     
         205 . The method of  claim 203 , wherein said preparative regimen comprises at least two immunosuppressants. 
     
     
         206 . The method of  claim 205 , wherein said at least two immunosuppressants are selected from the group consisting of cyclophosphamide, fludarabine, mechlorethamine, chlorambucil, melphalan, ifosfamide, thiotepa, hexamethylmelamine, busulfan, nitrosourea, methotrexate, azathioprine, mercaptopurine, procarbazine, dacarbazine, temozolomide, carmustine, lomustine, streptozocin, fluorouracil, dactinomycin, anthracycline, mitomycin C, bleomycin, mithramycin, mycophenolate mofetil, rapamycin, cyclosporin, deoxyspergualin, compstatin, methylprednisolone, leflunomide, abatacept, belatacept, sirolimus, everolimus, tacrolimus, daclizumab, basiliximab, infliximab, eculizumab, rituximab, alemtuzumab, tocilizumab, sarilumab, or olokizumab. 
     
     
         207 . The method of  claim 205 , wherein said at least two immunosuppressants are cyclophosphamide and fludarabine. 
     
     
         208 . The therapeutic product of  claim 194 , further comprising a dosage form of an immunostimulant. 
     
     
         209 . The therapeutic product of  claim 208 , wherein said immunostimulant comprises recombinant IL-2. 
     
     
         210 . The therapeutic product of  claim 194 , further comprising a dosage form of an infection prophylaxis agent. 
     
     
         211 . The therapeutic product of  claim 210 , wherein said infection prophylaxis agent comprises a herpes virus prophylaxis agent. 
     
     
         212 . The therapeutic product of  claim 194 , further comprising a dosage form of at least one antibiotic. 
     
     
         213 . The therapeutic product of  claim 212 , wherein said antibiotic comprises cephalosporin, quinolone, penicillin, rifamycin, lipiarmycin, sulfonamide, macrolide, lincosamide, tetracycline, daptomycin, glycylcycline, tigecycline, oxazolidione, linezolid, lipiarmycins, fidaxomicin, cephazolin, cephalothin, cephapirin, cephalethin, cephradin, cephadroxin, amoxicillin, ampicillin, cefuroxime, cephamandole, cephoxitin, cephaclor, cephrozil, loracarbef, carbenicillin, ticarcillin, cephixime, cephtriaxone, cephotaxime, cephtizoxime, cephtazidime, cephipime, cephtaroline, cephtobiprole, trimethoprim, sulfamethoxazole, or pentamidine