IMMUNOMODULATING TREATMENTS OF BODY CAVITIES
Provided herein are compositions and methods for treating cancer of a body cavity, including urinary tract cancer, by way of a combination of at least one immunomodulatory agent, such as a CTLA-4 antibody or TLR agonist, and optionally one chemotherapeutic agent, wherein one or more of the therapeutic agents are embedded in, and slowly released from, a biocompatible hydrogel composition.
1 . A method for treating a urinary tract cancer, comprising:
locally administering to a subject in need thereof a pharmaceutical composition comprising an admixture of:
i. a thermoreversible hydrogel comprising 20%-32% (w/w) of poloxamer and water; and
ii. a solution comprising about 100 mg to about 700 mg zalifrelimab,
wherein the pharmaceutical composition is formulated to provide sustained release of the zalifrelimab over a period of about 2 to about 24 hours.
2 . The method of claim 1 , wherein the thermoreversible hydrogel and solution comprising zalifrelimab are mixed prior to administration of the composition.
3 . The method of claim 1 , further comprising administering to the subject at least one additional therapeutic agent.
4 . The method of claim 3 , wherein the at least one additional therapeutic agent comprising imiquimod, mitomycin C, gemcitabine or any combination thereof.
5 . The method of claim 4 , wherein the zalifrelimab and the additional therapeutic agent are administered separately, with an optional wash between the administration of the two agents.
6 . The method of claim 1 , wherein the pharmaceutical composition administered produces a detectable zalifrelimab urine void concentration of at least 20 μg/mL after at least 2 hours of administration.
7 . The method of claim 1 , wherein the pharmaceutical composition is administered to the patient at least 6 times at about one-week intervals.
8 . The method of claim 7 , further comprising administering the pharmaceutical composition at least once quarterly from month 6 from the first administration until month 12 from the first administration of the pharmaceutical composition.
9 . The method of claim 1 , wherein the urinary tract cancer is a bladder cancer, and the bladder cancer is high-grade or low grade NMIBC, MIBC, or carcinoma in situ (CIS).
10 . The method of claim 1 , wherein the composition is administered prior to surgical removal of a tumor or after removal of a tumor.
11 . A method for treatment of a bladder cancer or regrowth of bladder cancer, comprising:
intravesically administering to a subject a pharmaceutical composition comprising an admixture of:
i. a thermoreversible hydrogel comprising poloxamer and water; and
ii. a solution comprising about 100 mg to about 700 mg zalifrelimab,
wherein the concentration of zalifrelimab in the pharmaceutical composition is 0.67-10 mg/ml;
wherein the thermoreversible hydrogel has a viscosity of not more than 5000 cP at 5° C., and a viscosity of 1×10 6 cP-9×10 7 cP at 17° C., and
wherein the hydrogel produces a voiding concentration of detectable zalifrelimab of at least 20-70 μg/mL in urine of the subject after at least 2 hours of administration,
thereby treating the cancer.
12 . The method of claim 11 , further comprising intravesically administering to the subject an additional therapeutic agent selected from imiquimod, mitomycin C or gemcitabine.
13 . The method of claim 11 , wherein the pharmaceutical composition is administered once weekly for 3-9 weeks.
14 . The method of claim 12 , wherein the additional therapeutic agent is administered prior to, concurrently with, or following administration of the pharmaceutical composition.
15 . A pharmaceutical composition, comprising:
i. a thermoreversible hydrogel comprising 20%-32% (w/w) of poloxamer and water; and
ii. about 30-100 mg/mL zalifrelimab formulated in a solution comprising 10-30 mM histidine, 200-300 mM sorbitol, 10-20 mM methionine, and 0.01-0.03% polysorbate 80, and is adjusted to a pH of 6-7.
16 . The pharmaceutical composition of claim 15 , wherein the thermoreversible hydrogel comprises 25%-32% (w/w) poloxamer, and the zalifrelimab solution comprises about 50 mg/mL zalifrelimab, 20 mM histidine, 250 mM sorbitol, 15 mM methionine, and 0.02% polysorbate 80.
17 . The pharmaceutical composition of claim 16 , wherein the final concentration of zalifrelimab in the pharmaceutical composition is 0.67-10 mg/mL; and wherein the said pharmaceutical composition has a viscosity of not more than 5000 cP at 5° C., and a viscosity of 1×10 6 cP-9×10 7 cP at 17° C.
18 . A method for treatment of a bladder cancer comprising:
(a) preparing a composition with an effective amount of a zalifrelimab solution into a thermoreversible hydrogel; and
(b) administering the composition to the bladder
wherein the thermoreversible hydrogel comprises: (i) 20% to 32% (w/w) poloxamer 407; (ii) 0.02% to 0.5% (w/w) hydroxypropylmethylcellulose; (iii) 0.5% to 1% (w/w) PEG-400; and (iv) water.
19 . The method of claim 18 , wherein the zalifrelimab has a concentration of 0.67-10 mg/mL.
20 . The method of claim 18 , further comprising intravesically administering to the subject an additional therapeutic agent selected from imiquimod, mitomycin C or gemcitabine.