Predictive test for patient benefit from antibody drug blocking ligand activation of the T-cell programmed cell death 1 (PD-1) checkpoint protein and classifier development methods
A method is disclosed of predicting cancer patient response to immune checkpoint inhibitors, e.g., an antibody drug blocking ligand activation of programmed cell death 1 (PD-1) or CTLA4. The method includes obtaining mass spectrometry data from a blood-based sample of the patient, obtaining integrated intensity values in the mass spectrometry data of a multitude of pre-determined mass-spectral features; and operating on the mass spectral data with a programmed computer implementing a classifier. The classifier compares the integrated intensity values with feature values of a training set of class-labeled mass spectral data obtained from a multitude of melanoma patients with a classification algorithm and generates a class label for the sample. A class label “early” or the equivalent predicts the patient is likely to obtain relatively less benefit from the antibody drug and the class label “late” or the equivalent indicates the patient is likely to obtain relatively greater benefit from the antibody drug.
1. A method of detecting a class label in a non-small cell lung cancer patient comprising:
a) conducting mass spectrometry on a blood-based sample of the patient and obtaining mass spectral data;
(b) obtaining integrated intensity values in the mass spectral data of a multitude of mass-spectral features, wherein the mass-spectral features include a multitude of features listed in Appendix A, Appendix B, or Appendix C; and
(c) operating on the mass spectral data with a programmed computer implementing a classifier;
wherein in the operating step the classifier compares the integrated intensity values with feature values of a reference set of class-labeled mass spectral data obtained from blood-based samples obtained from a multitude of cancer patients treated with an antibody drug blocking ligand activation of programmed cell death 1 (PD-1) with a classification algorithm and detects a class label for the sample.
2. The method of claim 1 , wherein the classifier is obtained from filtered mini-classifiers combined using a regularized combination method.
3. The method of claim 2 , wherein the regularized combination method comprises repeatedly conducting logistic regression with extreme dropout on the filtered mini-classifiers.
4. The method of claim 1 , wherein the classifier comprises an ensemble of tumor classifiers combined in a hierarchical manner.
5. The method of claim 1 , wherein the reference set comprise a set of class-labeled mass spectral data of a development set of samples having either the class label Early or the equivalent or Late or the equivalent, wherein the samples having the class label Early are comprised of samples having relatively shorter overall survival on treatment with nivolumab as compared to samples having the class label Late.
6. The method of claim 1 , wherein the mass spectral data is acquired from at least 100,000 laser shots performed on the sample using MALDI-TOF mass spectrometry.
7. The method of claim 1 , wherein the mass-spectral features are selected according to their association with the biological functions Acute Response and Wound Healing.
8. The method of claim 2 , wherein the mini-classifiers are filtered in accordance with criteria listed in Table 10.
9. The method of claim 1 , wherein the classifier is obtained from filtered mini-classifiers combined using a regularized combination method, and wherein the mini-classifiers are filtered in accordance with criteria listed in Table 10.
10. The method of claim 1 , wherein if the class label for the sample is Late or the equivalent then the patient is treated with an antibody drug blocking ligand activation of PD-1, and wherein if the class label for the sample is Early or the equivalent then the patient is treated with an antibody drug blocking ligand activation of PD-1 and an antibody drug targeting CTLA4.
11. The method of claim 10 , wherein the antibody drug blocking ligand activation of PD-1 is nivolumab, and the antibody drug targeting CTLA4 is ipilimumab.