Drug delivery compositions and uses thereof
Provided are drug delivery compositions and devices useful for the treatment and/or prevention of cancer and metastatic tumors. For example, a drug delivery device is provided that comprises a biodegradable scaffold carrying one or more anti-cancer therapeutic agents that activate the innate immune system (e.g., STING agonists) and/or the adaptive immune system (e.g., anti-PD-1 antibodies). The compositions and devices may include a cytokine (e.g., IL-15 superagonist). The drug delivery device can be implanted in the void volume of a resected tumor to prevent tumor regrowth and tumor metastasis. Also provided are methods of making the drug delivery compositions and devices as well as kits containing materials to provide the compositions and devices.
1. A method of treating cancer comprising a step of: intraoperative administration at a tumor resection site of a subject suffering from cancer: an effective amount of a combination of a biomaterial and an activator of Nucleotide-binding Oligomerization Domain-containing protein 1 (NOD1) and/or Nucleotide-binding Oligomerization Domain-containing protein 2 (NOD2), wherein the biomaterial is or comprises hyaluronic acid.
2. The method of claim 1 , wherein the biomaterial is characterized by a storage modulus of about 500 Pa to about 3000 Pa.
3. The method of claim 1 , wherein the step of administration excludes (i) adoptive transfer of T cells to the subject; (ii) administration of a tumor antigen to the subject; and/or (iii) administration of a microparticle to the subject.
4. The method of claim 1 , wherein the biomaterial is or comprises a hydrogel.
5. The method of claim 1 , wherein the biomaterial is or comprises a crosslinked hyaluronic acid.
6. The method of claim 5 , wherein the biomaterial is or comprises a hyaluronic acid crosslinked with a polyethylene glycol crosslinker.
7. The method of claim 1 , wherein the combination further comprises an activator of innate immunity, an activator of adaptive immunity, and/or a cytokine that modulates T cells, natural killer (NK) cells, monocytes, and/or dendritic cells.
8. The method of claim 1 , wherein the combination further comprises a cytokine that modulates T cells, NK cells, monocytes, and/or dendritic cells, and the cytokine is or comprises an IL-15 superagonist, IFN-α, IFN-β, IFN-γ, or combinations thereof.
9. The method of claim 1 , wherein the combination further comprises a chemotherapeutic agent with immunomodulatory ability.
10. The method of claim 1 , wherein the combination further comprises an anti-PD-1 antibody and/or an anti-CD137 antibody.
11. The method of claim 1 , wherein the biomaterial forms a matrix or depot and the activator of NOD1 and/or NOD2 is within the biomaterial.
12. The method of claim 11 , wherein the activator of NOD1 and/or NOD2 is released by diffusion through the biomaterial.
13. The method of claim 1 , wherein the biomaterial is biodegradable in vivo.
14. The method of claim 1 , wherein the biomaterial is characterized in that, when tested in vitro by placing a combination in PBS (pH 7.4), less than 100% of the activator of NOD1 and/or NOD2 is released within 3 hours from the biomaterial.
15. The method of claim 1 , wherein the biomaterial is characterized in that, when tested in vivo by implanting the combination at a mammary fat pad of a mouse subject, less than or equal to 50% of the activator of NOD1 and/or NOD2 is released in vivo 8 hours after the implantation.
16. The method of claim 1 , wherein the biomaterial is characterized in that it extends release of the activator of NOD1 and/or NOD2 so that, when assessed at 24 hours after administration, more activator of NOD1 and/or NOD2 is present in the tumor resection site than is observed when the activator of NOD1 and/or NOD2 is administered in solution.
17. The method of claim 1 , wherein the administration is by implantation.
18. The method of claim 1 , wherein the administration is by injection.
19. The method of claim 18 , wherein the administration comprises injecting one or more precursor components of the biomaterial and permitting the biomaterial to form at the site.
20. The method of claim 1 , wherein the tumor resection site is characterized by absence of gross residual tumor antigen.
21. The method of claim 1 , wherein the cancer is metastatic cancer.
22. The method of claim 21 , further comprising a step of monitoring at least one metastatic site in the subject after the administration.
23. The method of claim 1 , further comprising a step of, prior to the intraoperative administration,
resecting a tumor in the subject to form the tumor resection site.
24. The method of claim 1 , wherein the activator of NOD1 and/or NOD2 is present in the combination as a single therapeutic agent.