Methods and compositions comprising tumor suppressor gene therapy and immune checkpoint blockade for the treatment of cancer

Abstract

Provided herein are methods and compositions for treating cancer in an individual comprising administering to the individual an effective amount of at least one immune checkpoint inhibitor and a p53 and / or MDA-7 (IL24) gene therapy. Also provided herein are methods of enhancing anti-tumor efficacy by administering an extracellular matrix-degrading protein. Also provided herein are methods of enhancing anti-tumor efficacy by administering metronomic chemotherapy (for agents described above, 5FU+CTX+GM-CSF) in combination with a p53 and / or IL24 gene therapy.

Description

[0001] This application claims U.S. Provisional Application Serial No. 62 / 252,453 filed November 7, 2015, U.S. Provisional Application Serial No. 62 / 276,615 filed January 8, 2016, U.S. Provisional Application Serial No. 62 / 276,615 filed May 9, 2016 62 / 333,817, U.S. Provisional Application Serial No. 62 / 345,094, filed June 3, 2016, and U.S. Provisional Application Serial No. 62 / 408,879, filed October 17, 2016, each of which is hereby adopted in its entirety Incorporated by reference.

[0002] Incorporation of Sequence Listings

[0003] The Sequence Listing contained in the file named "SOBLP0143WO_ST25.txt", which is 3KB (as measured in Microsoft Windows) and was created on November 7, 2016, is submitted electronically with this article and is incorporated by reference Incorporated into this article.

[0004] Background of the invention 1. Technical field

[0005] The present invention relates generally to the fields of biology and medicine. More specifically, it relates ...

Examples

Embodiment 1

[0256] Example 1 - Ad-p53 or Ad-IL24 Tumor Suppressor Immunogene Therapy for Inducing Distant Effects and Reversing Resistance to Prior Immunotherapy

[0257] The efficacy of tumor suppressor immunogene therapy to induce distant effects in tumors resistant to previous immunotherapy was demonstrated in immunocompetent animal tumor models. Use the following treatments, doses and schedules:

[0258] Animals, Tumor Inoculation and Measurements: C57BL / 6 (B6) mice (6 to 8 weeks old) were used. B16F10 melanoma cells (ATCC, 5 × 10 5 cells / mouse) to form a "primary tumor". When the tumor size reaches about 50mm 3 Start treatment at , and this is referred to as treatment day 1. Tumor growth was monitored by measuring the length (L) and width (w) of the tumor, and the tumor volume was calculated using the following formula: Volume = 0.523L(w) 2 . Animals were monitored for up to 60 days and when tumors reached approximately 2000mm 3 time to execute.

[0259] viral vector : Re...

Embodiment 2

[0266] Example 2 - Combination Ad-p53 and Ad-IL24 Tumor Suppressor Immunogene Therapy for Tumors Resistant to Prior Immunotherapy

[0267] To determine the antitumor effect induced by the combination of tumor suppressors, Ad-p53 and Ad-IL24 were combined and administered as described above, using 50% of the original dose of each vector in the final therapeutic formulation. Such as( Figure 7 ) showed severe tumor progression in animals treated with anti-PD-1 monotherapy, whereas the combination of Ad-p53+Ad-IL24 showed reduced tumor growth. Reversal of anti-PD-1 resistance was observed in animals treated with the combination of Ad-p53+Ad-IL24+anti-PD1, which induced primary tumors, compared to anti-PD1 alone or Ad-p53+Ad-IL24 treatment Maximum reduction in volume. Statistical analysis of variance (ANOVA) comparison of tumor volumes for each treatment confirmed that the combined effect of Ad-p53+Ad-IL24+anti-PD-1 treatment was synergistic at day 14 of treatment (p-value=0.035...

Embodiment 3

[0268] Example 3 - Tumor Suppressor Immunogene Therapy in Combination with Chemotherapy and Cytokine Therapy for Tumors Resistant to Prior Immunotherapy

[0269] Animals, tumor inoculation and measurement, Ad-IL24 vector treatment and antibody treatment were used as described in Example 1.

[0270] chemotherapy and cytokine therapy : Treatment with chemotherapy (5FU and cyclophosphamide CTX) started on day 3 and consisted of a single injection of the drug (5FU and CTX), intraperitoneally (i.p.), using a 1 mL syringe. For 5FU, the dose is 50 mg / kg body weight; for cyclophosphamide, the dose is 80 mg / kg body weight. GM-CSF cytokine treatment was provided as recombinant murine GM-CSF dissolved in sterile ddH2O and adjusted to 1X PBS just prior to use. Animals were treated intraperitoneally and a dose of 0.5 μg / mouse was administered. Treatments were performed twice daily from days 3 to 13 of the study.

[0271] The therapeutic efficacy of 5-FU+CTX+GM-CSF combined with anti-P...

[0001] This application claims U.S. Provisional Application Serial No. 62 / 252,453 filed November 7, 2015, U.S. Provisional Application Serial No. 62 / 276,615 filed January 8, 2016, U.S. Provisional Application Serial No. 62 / 276,615 filed May 9, 2016 62 / 333,817, U.S. Provisional Application Serial No. 62 / 345,094, filed June 3, 2016, and U.S. Provisional Application Serial No. 62 / 408,879, filed October 17, 2016, each of which is hereby adopted in its entirety Incorporated by reference.

[0002] Incorporation of Sequence Listings

[0003] The Sequence Listing contained in the file named "SOBLP0143WO_ST25.txt", which is 3KB (as measured in Microsoft Windows) and was created on November 7, 2016, is submitted electronically with this article and is incorporated by reference Incorporated into this article.

[0004] Background of the invention 1. Technical field

[0005] The present invention relates generally to the fields of biology and medicine. More specifically, it relates ...

Examples

Embodiment 1

[0256] Example 1 - Ad-p53 or Ad-IL24 Tumor Suppressor Immunogene Therapy for Inducing Distant Effects and Reversing Resistance to Prior Immunotherapy

[0257] The efficacy of tumor suppressor immunogene therapy to induce distant effects in tumors resistant to previous immunotherapy was demonstrated in immunocompetent animal tumor models. Use the following treatments, doses and schedules:

[0258] Animals, Tumor Inoculation and Measurements: C57BL / 6 (B6) mice (6 to 8 weeks old) were used. B16F10 melanoma cells (ATCC, 5 × 10 5 cells / mouse) to form a "primary tumor". When the tumor size reaches about 50mm 3 Start treatment at , and this is referred to as treatment day 1. Tumor growth was monitored by measuring the length (L) and width (w) of the tumor, and the tumor volume was calculated using the following formula: Volume = 0.523L(w) 2 . Animals were monitored for up to 60 days and when tumors reached approximately 2000mm 3 time to execute.

[0259] viral vector : Re...

Embodiment 2

[0266] Example 2 - Combination Ad-p53 and Ad-IL24 Tumor Suppressor Immunogene Therapy for Tumors Resistant to Prior Immunotherapy

[0267] To determine the antitumor effect induced by the combination of tumor suppressors, Ad-p53 and Ad-IL24 were combined and administered as described above, using 50% of the original dose of each vector in the final therapeutic formulation. Such as( Figure 7 ) showed severe tumor progression in animals treated with anti-PD-1 monotherapy, whereas the combination of Ad-p53+Ad-IL24 showed reduced tumor growth. Reversal of anti-PD-1 resistance was observed in animals treated with the combination of Ad-p53+Ad-IL24+anti-PD1, which induced primary tumors, compared to anti-PD1 alone or Ad-p53+Ad-IL24 treatment Maximum reduction in volume. Statistical analysis of variance (ANOVA) comparison of tumor volumes for each treatment confirmed that the combined effect of Ad-p53+Ad-IL24+anti-PD-1 treatment was synergistic at day 14 of treatment (p-value=0.035...

Embodiment 3

[0268] Example 3 - Tumor Suppressor Immunogene Therapy in Combination with Chemotherapy and Cytokine Therapy for Tumors Resistant to Prior Immunotherapy

[0269] Animals, tumor inoculation and measurement, Ad-IL24 vector treatment and antibody treatment were used as described in Example 1.

[0270] chemotherapy and cytokine therapy : Treatment with chemotherapy (5FU and cyclophosphamide CTX) started on day 3 and consisted of a single injection of the drug (5FU and CTX), intraperitoneally (i.p.), using a 1 mL syringe. For 5FU, the dose is 50 mg / kg body weight; for cyclophosphamide, the dose is 80 mg / kg body weight. GM-CSF cytokine treatment was provided as recombinant murine GM-CSF dissolved in sterile ddH2O and adjusted to 1X PBS just prior to use. Animals were treated intraperitoneally and a dose of 0.5 μg / mouse was administered. Treatments were performed twice daily from days 3 to 13 of the study.

[0271] The therapeutic efficacy of 5-FU+CTX+GM-CSF combined with anti-P...

Images