Immunomodulating treatments of body cavities

Abstract

Described herein are compositions and methods for treating cancer of a body cavity, specifically urinary tract cancer, by way of a combination of at least two immunomodulatory agents, wherein one or more of the therapeutic agents are embedded in, and slowly released from, a biocompatible hydrogel composition.

We claim: 
     
         1 . A method of treatment for a cancer of an internal body cavity in a human subject, the method comprising:
 administering to a subject in need thereof a therapeutically effective amount of:
 a TLR agonist, and 
 an immune checkpoint modulator, 
   wherein at least one of the TLR agonist and the immune checkpoint modulator are provided in a thermo-reversible hydrogel composition comprising chitosan or at least one tri block copolymer having a general formula ABA or BAB copolymer, wherein A is a hydrophilic block and B is a hydrophobic block,   thereby treating the cancer of the body cavity.   
     
     
         2 . The method of  claim 1 , wherein the TLR agonist comprises an imidazoquinoline amine, a tetrahydroimidazoquinoline amine, an imidazopyridine amine, a 1,2-bridged imidazoquinoline amine, a 6,7-fused cycloalkylimidazopyridine amine, an imidazonaphthyridine amine, a tetrahydroimidazonaphthyridine amine, an oxazoloquinoline amine, a thiazoloquinoline amine, an oxazolopyridine amine, a thiazolopyridine amine, an oxazolonaphthyridine amine, a thiazolonaphthyridine amine, TMX101, MEDI9197, NKTR-262, TMX 201, TMX 202, TMX-30X, TMX302, Motolimod, DUK-CPG-001, IMO-2055 (EMD1201081), CpG-28, AST-008, IMO-2125, CMP-001, agatolimod, SD-101, MGN1703, G100, BCG, QS-21, or AS15. 
     
     
         3 . The method of  claim 1 , wherein the immune checkpoint modulator comprises anti-PD1, anti-PDL1, anti-CTLA4, anti-KIR, anti-LAG3, anti-VISTA, anti-TIM3, anti-B7-H3, anti-B7-H4, or anti-BTLA. 
     
     
         4 . The method of  claim 3  wherein the immune checkpoint modulator is an antagonistic antibody selected from the group consisting of: Pembrolizumab (Keytrude, MK-3475), Cemiplimab (AGEN-2034), Nivolumab (Opdivo, BMS-936558), Pidilizumab (CT-011), MEDI0680 (AMP514), TSR-042, AMP-224, Durvalumab (MEDI4736), Avelumab (MSB0010718C), Atezolizumab (MPDL3280A), MDX1105 (BMS-936559), Ipilimumab (Yervoy), Tremelimumab (CP-675,206), Lirlumab (BMS986015), IPH2101, Relatlimab (BMS986016), IMP321, TSR-033, JNJ-61610588, CA-170, BMS-986207, TSR022, Enoblituzumab (MGA271), MGD009, AGEN-1884, AGEN-2041 (AGEN-1181), ADU-1604, AK 104, ALPN-202, BCD-145, BMS-986249, BPI-002, CBT-509, ADU-1604, ATOR 1144, ATOR-1015 and DS-5573a. 
     
     
         5 . The method of  claim 1 , wherein the immune checkpoint modulator is an agonist antibody that binds to an antigen selected from the group consisting of 41BB (CD137), OX40 (CD134), CD28, ICOS (CD278) or CD40. 
     
     
         6 . The method of  claim 5 , wherein the antibody is selected from the group consisting of Utomilumab (PF05082566), Urelumab (BMS663516), MEDI6469, PF04518600 (PF-8600), MOXRO916, AMG228, GSK3174998, TGN1412 (TAB08), MEDI-570, GSK3359609, CP870890 and APX005M. 
     
     
         7 . The method of  claim 1 , wherein the tri block copolymer having an ABA formula is EPO/PPO/EPO block copolymer. 
     
     
         8 . The method of  claim 7 , wherein the tri block copolymer having an ABA formula has an average molecular weight of 8500-16000DA, inclusive. 
     
     
         9 . The method of  claim 7 , wherein the tri block copolymer having ABA formula is Poloxamer. 
     
     
         10 . The method of  claim 9 , wherein the Poloxamer comprises Poloxamer 407, Poloxamer 188, Poloxamer124, Poloxamer 237, or Poloxamer 338. 
     
     
         11 . The method of  claim 1 , wherein the cancer is selected from the group consisting of bladder cancer, urinary tract cancer, upper urinary tract cancer, renal cancer, gastrointestinal cancer, colon cancer, rectal cancer, and female reproductive system cancer. 
     
     
         12 . The method of  claim 1 , wherein the thermoreversible hydrogel composition further comprises a mucoadhesive polymer. 
     
     
         13 . The method of  claim 1 , wherein the thermoreversible hydrogel composition comprises 15% (w/w)-40% (w/w) poloxamer 407. 
     
     
         14 . The method of  claim 3  wherein the CTLA4 inhibitor is Ipilimumab or Tremelimuab provided at a concentration 1 (mg/Kg B.W) to 50 (mg/Kg B.W), wherein the PDL-1 inhibitor is Atezolizumab, Durvalumab, or Avelumab provided at a concentration of 5 (mg/Kg B.W) to 70 (mg/Kg B.W), and wherein the PD-1 inhibitor is Pembrolizumab or Nivolumab provided at a concentration of 0.5 (mg/Kg B.W) to 50 (mg/Kg B.W). 
     
     
         15 . The method of  claim 1 , wherein the TLR agonist is administered intravesically. 
     
     
         16 . The method of  claim 1 , wherein the immune checkpoint modulator is administered systemically or locally. 
     
     
         17 . The method of  claim 1 , wherein the TLR agonist and the immune checkpoint modulator are provided in the thermo-reversible hydrogel intravesically into the internal body cavity. 
     
     
         18 . A method for inhibiting re-growth of a cancer of an internal body cavity in a human subject, the method comprising:
 administering to a subject in need thereof a therapeutically effective amount of:
 a TLR agonist, and 
 an immune checkpoint modulator, 
   wherein at least one of the TLR agonist and the immune checkpoint modulator are provided in a thermo-reversible hydrogel composition comprising chitosan or at least one tri block copolymer having a general formula ABA or BAB copolymer, wherein A is a hydrophilic block and B is a hydrophobic block,   and wherein the TLR agonist and immune checkpoint modulator are administered to the subject subsequent to a treatment for the cancer which removed or decreased the amount of the cancer in the subject,   thereby inhibiting the regrowth cancer of the body cavity.   
     
     
         19 . The method for treating a cancer of an internal body cavity of  claim 1 , comprising administering to the subject:
 (a) a therapeutically effective amount of a TLR agonist, and   (b) a therapeutically effective amount of an immune checkpoint modulator selected from the group consisting of anti-PD1, anti-PDL1, and anti-CTLA4;   wherein (a) and (b) are provided separately in a thermo-reversible hydrogel composition comprising a chitosan or tri block copolymer having a general formula ABA or BAB, wherein A is a hydrophilic block and B is a hydrophobic block, and administered locally into the internal body cavity.   
     
     
         20 . A composition comprising:
 a TLR agonist, and   an immune checkpoint modulator,   
       wherein at least one of the TLR agonist and the immune checkpoint modulator are formulated in a thermo-reversible hydrogel composition comprising chitosan or at least one tri block copolymer having a general formula ABA or BAB copolymer, wherein A is a hydrophilic block and B is a hydrophobic block.