PREDICTING PATIENT RESPONSIVENESS TO IMMUNE CHECKPOINT INHIBITORS
The invention is directed to a method of predicting clinical response of a patient to treatment of a cancer by an immune checkpoint pathway inhibitor, such as an anti-CTLA-4 or anti-PD-1 antibody binding compound. In one aspect the method comprises generating pre- and post-treatment clonotype profiles, determining a number of clonotypes that decrease in frequency between the first and second clonotype profiles, and predicting a lack of responsiveness in the patient to the treatment whenever the number of clonotypes that decrease in frequency is greater than a predetermined value.
1 . A method of predicting clinical response of a patient to treatment of a cancer by an immune checkpoint pathway inhibitor, the method comprising the steps of:
(a) generating a first clonotype profile from recombined T cell receptor genes or nucleic acids transcribed therefrom from a first patient sample taken before treatment by an immune checkpoint pathway inhibitor;
(b) generating a second clonotype profile from recombined T cell receptor genes or nucleic acids transcribed therefrom from a second patient sample taken during or after treatment by an immune checkpoint pathway inhibitor;
(c) determining a number of clonotypes that decrease in frequency between the first and second clonotype profiles; and
(d) predicting a lack of responsiveness in the patient to the treatment whenever the number of clonotypes that decrease in frequency is greater than a predetermined value.
2 . The method of claim 1 wherein clonotype frequencies of said first clonotype profile greater than 10 −6 form a baseline set of clonotypes that are compared to clonotype frequencies of a clonotype profile of a successive sample.
3 . The method of claim 2 wherein said predetermined value is a number of clonotypes in said baseline set in the range of from 10 to 1000.
4 . The method of claim 2 wherein said predetermined value is a number corresponding to at least twenty-five percent of said baseline set.
5 . The method of claim 1 wherein said immune checkpoint pathway inhibitor is CTLA-4 or PD-1.
6 . The method of claim 5 wherein said immune checkpoint pathway inhibitor is CTLA-4.
7 . A method of predicting clinical response of a patient to treatment of a cancer by a CTLA-4 inhibitor, the method comprising the steps of:
(a) generating a first clonotype profile from recombined T cell receptor genes or nucleic acids transcribed therefrom from a first patient sample taken before treatment by a CTLA-4 inhibitor;
(b) generating a second clonotype profile from recombined T cell receptor genes or nucleic acids transcribed therefrom from a second patient sample taken during or after treatment by a CTLA-4 inhibitor;
(c) determining a number of clonotypes that decrease in frequency between the first and second clonotype profiles; and
(d) predicting a lack of responsiveness in the patient to the treatment whenever the number of clonotypes that decrease in frequency is greater than a predetermined value.
8 . The method of claim 7 wherein each of said first and second clonotype profiles comprise at least 10 3 clonotypes and said predetermined value is in a range of from 10 to 1000 clonotypes.
9 . The method of claim 7 wherein said decrease in frequency is any statistically significant decrease.
10 . The method of claim 7 wherein said number is based on decreases in frequencies of clonotypes that each have a frequency in said first clonotype profile of at least 10 −5 .
11 . The method of claim 7 wherein said decrease in frequency is at least a two-fold decrease.
12 . The method of claim 7 wherein said first patient sample is taken from said patient within one week prior to initiation of said treatment.
13 . The method of claim 12 wherein said first patient sample is taken at the time treatment is initiated.
14 . The method of claim 7 wherein said second patient sample is taken from said patient within three months after initiation of said treatment.
15 . The method of claim 14 wherein said second patient sample is taken from said patient within one month after initiation of said treatment.
16 . The method of claim 7 wherein said CTLA-4 inhibitor is a therapeutic antibody.
17 . The method of claim 16 wherein said therapeutic antibody is ipilimumab or tremelimumab or an antibody binding compound derived therefrom.
18 . The method of claim 7 wherein said cancer is a prostate cancer or a melanoma.
19 . A method of selecting a patient having a cancer for treatment by a CTLA-4 inhibitor, the method comprising the steps of:
(a) generating a first clonotype profile from recombined T cell receptor genes or nucleic acids transcribed therefrom from a first patient sample taken before treatment by a CTLA-4 inhibitor;
(b) generating a second clonotype profile from recombined T cell receptor genes or nucleic acids transcribed therefrom from a second patient sample taken during or after treatment by a CTLA-4 inhibitor;
(c) determining a number of clonotypes that decrease in frequency between the first and second clonotype profiles; and
(d) selecting the patient for treatment with a CTLA-4 inhibitor whenever the number of clonotypes that decrease in frequency is below a predetermined value.
20 . The method of claim 19 wherein clonotype frequencies of said first clonotype profile greater than 10 −6 form a baseline set of clonotypes that are compared to clonotype frequencies of a clonotype profile of a successive sample.