Immunomodulation after locoregional anti-tumoral treatment
The present invention concerns a thermosensitive polymeric hydrogel comprising at least one thermosensitive copolymer, one aqueous solution, and a mucoadhesive excipient, wherein said thermosensitive polymeric hydrogel further comprises at least one immunostimulatory adjuvant and/or at least one cytokine and/or at least one chemokine and/or atleast one heat shockprotein. Another object of the invention is a thermosensitive polymeric hydrogel according to the invention for use in the treatment of tumors or metastasis in a subject having a cancer, preferably a metastatic cancer.
1. A thermosensitive mucoadhesive polymeric hydrogel comprising:
at least one thermosensitive copolymer, consisting of poloxamer 407 at a concentration of 21% w/v, in one aqueous solution; and
xantham gum at a concentration of 0.1% w/v;
wherein said thermosensitive polymeric hydrogel further comprises at least one immunostimulatory adjuvant and at least one cytokine and/or at least one chemokine and/or at least one heat shock protein, and wherein said hydrogel presents a gelification temperature between 21° C. and 28° C., and can be administered as a flowable liquid but will gelify on the tissue of interest.
2. A method for the treatment of tumors or metastasis in a subject having a cancer, comprising the administration of a thermosensitive mucoadhesive polymeric hydrogel to said subject, wherein said hydrogel comprises:
at least one thermosensitive copolymer consisting of poloxamer 407, at a concentration of 21% w/v, in one aqueous solution; and
xantham gum at a concentration of 0.1% w/v;
wherein said thermosensitive polymeric hydrogel further comprises at least one immunostimulatory adjuvant and at least one cytokine and/or at least one chemokine and/or at least one heat shock protein, and wherein said hydrogel presents a gelification temperature between 21° C. and 28° C., and can be administered as a flowable liquid but will gelify on the tissue of interest.
3. A thermosensitive mucoadhesive polymeric hydrogel according to claim 1 , wherein said thermosensitive polymeric hydrogel allows controlling release of said immunostimulatory adjuvant and said cytokine and/or said chemokine and/or said heat shock protein, under physiological conditions, over a period from at least 12 hours to 12 days.
4. A method for the treatment of tumors or metastasis according to claim 2 , wherein said cancer is selected from colorectal cancer, hepatocellular carcinoma, melanoma, kidney cancer, lung cancer, breast cancer, pancreatic cancer, and bone cancer.
5. A thermosensitive mucoadhesive polymeric hydrogel according to claim 1 , wherein said immunostimulatory adjuvant is selected from the group consisting of:
Bacillus Calmette-Guérin (BCG) and/or at least one of its purified proteins;
(ii) CpG oligodeoxynucleotides (CpG ODN), or any attenuated bacterial or viral agents and derivatives thereof having a specific or a non-specific anti-tumoral activity;
(iii) a heat killed bacteria selected from: Mycobacterium tuberculosis (HKMT), Salmonella typhimurium (HKST), Listeria monocytogenes (HKLM), Mycobacterium vaccae, Mycobacterium obuense and inactivated Streptococcus pyogenes and combinations thereof, or
(iv) an Lps analog selected from: MPLA (monophosphoryl lipid A), G100 (glucopranosyl lipid A), and combinations thereof; and
(v) a synthetic analog selected from: Imiquimod, mifamurtide, and combinations thereof.
6. A thermosensitive mucoadhesive polymeric hydrogel according to claim 1 , wherein said cytokine and/or said chemokine and/or said heat shock protein are selected from the group consisting of: granulocyte macrophage colony stimulating factor (GMCSF), granulocyte colony stimulating factor (GCSF), IL 12, Interferon γ, TNF α, GP96, heat shock protein (HSP), and HSP70.
7. A method for the treatment of cancer tumors or metastasis according to claim 2 , wherein said thermosensitive mucoadhesive polymeric hydrogel is used along with:
(i) a thermal locoregional treatment, or
(ii) cryotherapy, or
(iii) embolization, and/or
(iv) an anti-tumoral treatment,
and wherein said thermosensitive polymeric hydrogel is administered concomitantly or sequentially.
8. A method for the treatment of cancer tumors or metastasis according to claim 2 , wherein said thermosensitive polymeric hydrogel is administered concomitantly with a Radio Frequency Ablation (RFA) and sequentially with a systemic immune check point inhibitor that is selected from the group consisting of: anti-PD1, anti-CTLA4, anti-PDL1, anti-TIM3, anti-LAG3, anti-IDO, anti-Kir, anti-blta, and combinations thereof.
9. A kit comprising:
(i) a thermosensitive mucoadhesive polymeric hydrogel comprising:
at least one thermosensitive copolymer consisting of poloxamer 407 in a concentration of 21% w/v, in one aqueous solution; and
xantham gum in a concentration of 0.1% w/v,
wherein said hydrogel presents a gelification temperature between 21° C. and 28° C., and can be administered as a flowable liquid but will gelify on the tissue of interest;
(ii) at least one immunostimulatory adjuvant selected from the group consisting of:
Bacillus Calmette Guerin BCG and/or at least one of its purified proteins;
CpG oligodeoxynucleotides (CpG ODN);
attenuated bacterial, viral agents and derivatives thereof having a specific or a non-specific anti-tumoral activity;
heat killed bacteria selected from: Mycobacterium tuberculosis (HKMT), Salmonella typhimurium (HKST), Listeria monocytogenes (HKLM), Mycobacterium vaccae, Mycobacterium obuense and inactivated Streptococcus pyogenes , and combinations thereof; or
an Lps analog selected from: MPLA (monophosphoryl lipid A), G100 (glucopranosyl lipid A) and combinations thereof; and
synthetic analog selected from the group consisting of: Imiquimod, mifamurtide, and combinations thereof;
(iii) at least one cytokine and/or at least one chemokine and/or at least one heat shock protein selected from the group consisting of: granulocyte macrophage colony stimulating factor (GMCSF), granulocyte colony stimulating factor (GCSF), IL12, Interferon γ, TNFα, GP96, heat shock protein (HSP), and HSP70.
10. A method of treatment according to claim 2 , wherein said thermosensitive mucoadhesive polymeric hydrogel allows controlling release of said immunostimulatory adjuvant and/or said cytokine and/or said chemokine and/or said heat shock protein, under physiological conditions, over a period from at least 12 hours to 12 days.
11. A method of treatment according to claim 2 , wherein said immunostimulatory adjuvant is selected from the group consisting of:
Bacillus Calmette-Guérin BCG and/or at least one of its purified proteins;
(ii) CpG oligodeoxynucleotides (CpG ODN), or any attenuated bacterial or viral agents and derivatives thereof having a specific or a non-specific anti-tumoral activity;
(iii) a heat killed bacteria selected from: Mycobacterium tuberculosis (HKMT), Salmonella typhimurium (HKST), Listeria monocytogenes (HKLM), Mycobacterium vaccae, Mycobacterium obuense and inactivated Streptococcus pyogenes , and combinations thereof, or
(iv) an Lps analog selected from: MPLA (monophosphoryl lipid A), G100 (glucopranosyl lipid A) and combinations thereof; and
(v) a synthetic analog selected from: Imiquimod, mifamurtide, and combinations thereof.
12. A method of treatment according to claim 2 , wherein said cytokine and/or said chemokine and/or said heat shock protein are selected from the group consisting of: granulocyte macrophage colony stimulating factor (GMCSF), granulocyte colony stimulating factor (GCSF), IL 12, Interferon γ, TNF α, GP96, heat shock protein (HSP), and HSP70.
13. A thermosensitive mucoadhesive polymeric hydrogel according to claim 1 , wherein the sol-gel transition of the thermosensitive copolymer is reversible in the hydrogel.