Maximizing T-cell memory and compositions and methods therefor
Contemplated treatments and methods produce substantially increased quantities of memory T-cells and a persistent immune response by subcutaneous and/or subdermal co-administration of (1) a vector comprising a recombinant nucleic acid that encodes a cancer associated epitope, a cancer specific epitope, and/or a neoepitope, (2) an immune stimulating cytokine, and (3) a checkpoint inhibitor. Most typically, the co-administration is performed at substantially the same location, preferably within 1-21 days from each other, and the vector is an adenoviral expression vector, for example, included in a viral particle such as an AdV5 virus with a deletion of the E2b gene.
1. A method of stimulating development of memory T-cells against at least one of a cancer associated epitope, a cancer specific epitope, and neoepitope in a patient, the method comprising:
co-administering by subcutaneous or subdermal injection:
(1) a vector with a recombinant nucleic acid that encodes the at least one of the cancer associated epitope, the cancer specific epitope, and the neoepitope;
(2) an IL-15 superagonist;
(3) a checkpoint inhibitor selected from an anti-PD1 antibody and an anti-PDL1 antibody;
wherein the step of co-administering is performed under a protocol such that the vector, the cytokine, and the checkpoint inhibitor are present in the patient in measurable quantities at the same time.
2. The method of claim 1 wherein the vector is an adenoviral expression vector.
3. The method of claim 2 further comprising a step of administering a low-dose chemotherapy and/or radiation to stimulate overexpression of the cancer associated epitope, the cancer specific epitope, the neoepitope, and/or a NKG2D ligand.
4. The method of claim 2 further comprising a step of administering a drug that reduces number or function of Tregs, M2 macrophages and/or myleoid derived suppressor cells.
5. The method of claim 4 wherein the drug is gemcitabine, nab-paclitaxel, or a phosphodiesterase-5 (PDES) inhibitor.
6. The method of claim 2 further comprising a step of administering a drug that increases T-cells when given metronomically in low doses.
7. The method of claim 6 wherein the drug is cyclophosphamide or 5-fluorouracil.
8. The method of claim 2 further comprising a step of administering an additional chemokine.
9. The method of claim 2 further comprising a step of administering a cell-based composition comprising an immune competent cell.
10. The method of claim 9 wherein the immune competent cell is a T-cell, optionally having a chimeric antigen receptor, or an NK cell, optionally having a high-affinity CD16 or a chimeric antigen receptor.
11. The method of claim 2 wherein the recombinant nucleic acid further encodes at least one of an additional cytokine, a co-stimulatory molecule, and a checkpoint inhibitor.
12. The method of claim 11 wherein the co-administration of the at least one of the additional cytokine and the checkpoint inhibitor is by expression from the recombinant nucleic acid.
13. The method of claim 2 wherein the adenoviral expression vector is an adenovirus type 5 virus with an E2b gene region deletion.
14. The method of claim 2 wherein the vector, the cytokine, and the checkpoint inhibitor are injected at substantially the same site within one to five days.
15. A method of eliciting a durable immune response against a tumor expressing at least one of a cancer associated epitope, a cancer specific epitope, and neoepitope in a patient, comprising:
co-administering by subcutaneous or subdermal injection:
(1) a vector with recombinant nucleic acid that encodes the at least one of the cancer associated epitope, the cancer specific epitope, and the neoepitope;
(2) an IL-15 superagonist;
(3) a checkpoint inhibitor selected from an anti-PD1 antibody and an anti-PDL1 antibody;
wherein the step of co-administering is performed to trigger formation or propagation of memory T-cells in an amount sufficient to produce a persistent immune response against the tumor.
16. The method of claim 15 wherein the adenoviral expression vector particle is an adenovirus type 5 virus with an E2b gene region deletion.
17. The method of claim 16 further comprising at least one of a step of
(1) administering low-dose chemotherapy and/or radiation under a protocol effective to stimulate overexpression of a cancer associated epitope, a cancer specific epitope, a neoepitope, and/or a NKG2D ligand;
(2) administering a drug that reduces production of Tregs, M2 macrophage, and/or myleoid derived suppressor cells;
(3) administering a drug that increases T-cells when given metronomically in low doses;
(4) administering a chemokine; and
(5) administering a cell-based composition comprising an immune competent cell.
18. The method of claim 17 further comprising at least two of a step of
(1) administering low-dose chemotherapy and/or radiation under a protocol effective to stimulate overexpression of a cancer associated epitope, a cancer specific epitope, a neoepitope, and/or a NKG2D ligand;
(2) administering a drug that reduces production of Tregs, M2 macrophage, and/or myleoid derived suppressor cells;
(3) administering a drug that increases T-cells when given metronomically in low doses;
(4) administering a chemokine; and
(5) administering a cell-based composition comprising an immune competent cell.
19. The method of claim 18 further comprising at least three of a step of
(1) administering low-dose chemotherapy and/or radiation under a protocol effective to stimulate overexpression of a cancer associated epitope, a cancer specific epitope, a neoepitope, and/or a NKG2D ligand;
(2) administering a drug that reduces production of Tregs and/or myleoid derived suppressor cells;
(3) administering a drug that increases T-cells when given metronomically in low doses;
(4) administering a chemokine; and
(5) administering a cell-based composition comprising an immune competent cell.
20. The method of claim 16 wherein the vector, the cytokine, and the checkpoint inhibitor are injected at substantially the same site within 1-21 days.