Methods of identifying patients responsive to immunotherapeutic strategies
The invention includes a method of determining whether a mammal's cancerous tumor is associated with a hypermutator phenotype (i.e., harboring a large number of mutations) for the DNA Polymerase epsilon (POLE) gene as compared to normal cells. The invention further includes a method of selecting patients harboring an immunogenic tumor that is responsive to immunotherapy.
1. A method of treating a mammal with a cancerous tumor, wherein the method comprises:
i. sequencing the nucleotide sequence of DNA polymerase epsilon (POLE) gene from a sample isolated from the mammal's cancerous tumor;
ii. comparing the nucleotide sequence of the POLE gene from the sample isolated from the mammal's cancerous tumor and the corresponding nucleotide sequence from a control sample,
iii. detecting one or more mutations in the POLE gene from the mammal's cancerous tumor indicating that the mammal carries a high mutator phenotype; and,
iv. administering to the mammal, at least one treatment selected from the group consisting of Ipilimumab and autologous-monocyte derived dendritic cells loaded with cancer cell lysate.
2. The method of claim 1 , wherein the mutation in POLE from the mammal's cancerous tumor includes at least one base mutation selected from the group consisting of a base deletion, base insertion, base duplication, and base substitution.
3. The method of claim 2 , wherein the base mutation generates a synonymous or non-synonymous change in the corresponding protein or enzyme.
4. The method of claim 3 , wherein the protein or enzyme associated with the base mutation has distinct activity from the protein or enzyme from a control sample.
5. The method of claim 1 , wherein the cancerous tumor is a cancer selected from the group consisting of lung, colon, breast, prostate, endometrial, ovarian, melanoma, kidney, liver, and lymphoma.
6. The method of claim 1 , wherein the detection of a high mutator phenotype in the mammal's cancerous tumor is indicative of a high immunogenicity in the mammal.
7. The method of claim 1 , further comprising administering to the mammal an additional treatment selected from the group consisting of a chemotherapeutic treatment, an anti-cell proliferating treatment and any combination thereof.
8. The method of claim 1 , wherein the mammal is a human.