Cancer immunotherapy
We formulated multiple TLR agonists into GVAX (lethally irradiated tumor cell vaccines engineered to secrete GM-CSF). Specifically, GLA and R848, TLR4 and TLR7/8 agonists found to be safe in patients, were formulated with GVAX (TEGVAX—for TLR agonists enhanced GVAX), and this formulation was effective in producing anti-tumor responses in 3 different preclinical models, including palpable B16. These anti-tumor responses were correlated with increased CD4 and CD8 T-cells that can secrete IFNγ circulating in the tumor microenvironment as well as significantly higher level of p15E specific CTL mediated cell killing in mice treated with TEGVAX in comparison to controls. When combined with anti-PD-1 antibody, TEGVAX was able to induce regression of established B16 tumors.
1. A composition comprising:
cytokine-expressing, proliferation incompetent, whole cancer cells;
an anti-PD-1 antibody that specifically binds to human Programmed Death 1 (PD-1); and
a TLR (toll like receptor) agonist;
wherein the whole cancer cells are formulated with the TLR agonist.
2. The composition of claim 1 wherein the cytokine is GM-CSF (Granulocyte-macrophage colony stimulating factor).
3. The composition of claim 1 wherein the whole cancer cells are autologous to the patient.
4. The composition of claim 1 wherein the whole cancer cells are formulated with a TLR7/8 agonist.
5. The composition of claim 1 wherein the whole cancer cells are formulated with a TLR4 agonist.
6. The composition of claim 1 wherein the whole cancer cells are formulated with a TLR4 and a TLR7/8 agonist.
7. The composition of claim 1 wherein the TLR agonist is selected from the group consisting of GLA, R848, and a combination thereof.
8. The composition of claim 1 wherein the cancer cells are melanoma cells.
9. The composition of claim 1 wherein the TLR agonist and whole tumor cells are formulated with an emulsion vehicle.
10. The composition of claim 1 wherein the TLR agonist and whole tumor cells are formulated with Lipofectamine™.
11. The composition of claim 1 wherein the TLR agonist and whole tumor cells are formulated with a cationic lipid.
12. A method comprising:
administering to a cancer patient immunotherapeutic agents:
cytokine-expressing, proliferation incompetent, whole cancer cells;
an anti-PD-1 antibody that specifically binds to human Programmed Death 1 (PD-1); and
a TLR (toll like receptor) agonist;
wherein the whole cancer cells are formulated with the TLR agonist.
13. The method of claim 12 wherein the cytokine is GM-CSF (Granulocyte-macrophage colony stimulating factor).
14. The method of claim 12 wherein the whole cancer cells are autologous to the patient.
15. The method of claim 12 wherein the whole cancer cells are formulated with a TLR7/8 agonist.
16. The method of claim 12 wherein the whole cancer cells are formulated with a TLR4 agonist.
17. The method of claim 12 wherein the whole cancer cells are formulated with a TLR4 and a TLR7/8 agonist.
18. The method of claim 12 wherein the TLR agonist is selected from the group consisting of GLA, R848, and a combination thereof.
19. The method of claim 12 wherein the whole cancer cells are melanoma cells.
20. The method of claim 12 wherein the TLR agonist and whole tumor cells are formulated with an emulsion vehicle.
21. The method of claim 12 wherein the TLR agonist and whole tumor cells are formulated with Lipofectamine™.
22. The method of claim 12 wherein the TLR agonist and whole tumor cells are formulated with a cationic lipid.
23. A kit comprising agents:
cytokine-expressing, proliferation incompetent, whole cancer cells;
an anti-PD-1 antibody that specifically binds to human Programmed Death 1 (PD-1); and
a TLR (toll like receptor) agonist.
24. The kit of claim 23 further comprising instructions for administering and/or formulating the agents.
25. The kit of claim 23 further comprising an emulsion vehicle.
26. The kit of claim 23 further comprising Lipofectamine™.
27. The kit of claim 23 further comprising a cationic lipid.