Enhanced adoptive cell therapy

A method of increasing the efficacy of adoptive T-cell therapy in a subject comprising:

• intratumorally administering an oncolytic adenoviral vector to a subject who has been administered an adoptive T-cell therapeutic composition, wherein said oncolytic adenoviral vector is an adenovirus serotype 5 (Ad5) vector comprising:
• i) a 5/3 chimeric fiber knob,
• ii) E2F1 promoter for tumor specific expression of E1A,
• iii) a 24 bp deletion (D24) in the Rb binding constant region 2 of adenoviral E1,
• iv) a nucleic acid sequence deletion of viral gp19k and 6.7 k reading frames, and
• v) a nucleic acid sequence encoding at least TNFalpha or IL-2 transgene in the place of the deleted 19k/6.7K in the E3 region resulting in replication-associated control of transgene expression under the viral E3 promoter, wherein said vector infects tumor cells in said tumor and expresses the TNFalpha or IL-2 transgene in the infected tumor cells, and wherein the infection with said vector results in enhanced trafficking of T-cells to the tumor and consequently in decreased tumor size when compared to non-infected tumor cells, and wherein the infected tumor cells are defective in the Rb-p16 pathway, thereby increasing the efficacy of adoptive T-cell therapy.

A method of treating a tumor in a subject, wherein the method comprises intratumoral administration of an oncolytic adenoviral vector to a subject comprising a tumor, wherein said oncolytic adenoviral vector comprises:

• i) an adenovirus serotype 5 (Ad5) nucleic acid backbone comprising a 5/3 chimeric fiber knob;
• ii) E2F1 promoter for tumor specific expression of El A;
• iii) a 24 bp deletion (D24) in the Rb binding constant region 2 of adenoviral E1;
• iv) a nucleic acid sequence deletion of viral gp19k and 6.7 k reading frames;
• and
• v) a nucleic acid sequence encoding TNFalpha and IL-2 transgenes in the place of the deleted gp19k/6.7K in the E3 region resulting in replication-associated control of transgene expression under the viral E3 promoter, wherein the adenoviral vector comprises an internal ribosomal entry site (IRES) or a ribosome shunt site 2A between the two transgenes, wherein said vector infects tumor cells in said tumor and expresses the TNFalpha and IL-2 transgenes in the infected tumor cells, and wherein the infection with said vector results in enhanced trafficking of T-cells to the tumor and consequently in decreased tumor size when compared to non-infected tumor cells, and wherein the infected tumor cells are defective in the Rb-p16 pathway.

A method of treating tumors in a subject, wherein the method comprises:

• separate administration of an adoptive T-cell therapeutic composition and an oncolytic adenoviral vector to a subject, wherein the administration of the T-cell therapeutic composition is intravenous, intratumoral and/or intraperitoneal, wherein the administration of the oncolytic adenoviral vector is intratumoral and wherein said oncolytic adenoviral vector is an adenovirus serotype 5 (Ad5) vector comprising
• a 5/3 chimeric fiber knob,
• E2F1 or CMV promoter for tumor specific expression of E1A,
• a 24 bp deletion (D24) in the Rb binding constant region 2 of adenoviral E1,
• a nucleic acid sequence deletion of viral gp19k and 6.7 k reading frames, and
• a nucleic acid sequence encoding TNFalpha and IL-2 transgenes in the place of the deleted gp19k/6.7K in the E3 region resulting in replication-associated control of transgene expression under the viral E3 promoter,
• wherein the adenoviral vector comprises an internal ribosomal entry site (IRES) or a ribosome shunt site 2A between the two transgenes,
• wherein said vector infects tumor cells in said tumor and express TNFalpha and IL-2 transgenes in the infected tumor, and wherein the infection with said vector results in enhanced trafficking of T-cells to the tumor and consequently in decreased tumor size when compared to non-infected tumor cells, and
• wherein the infected tumor cells are defective in the Rb-p16 pathway.