Embodiments of the present invention provide diagnostic markers of immunosenescence and methods of identifying individuals with impaired immune function based on a combination of such markers obtained from various analyzes, primarily from blood, testing immune function including the analysis of immune cell subset frequencies, gene expression, cytokine and chemokine levels, and signaling responses to stimulation with cytokines (cytokine response). Particular combinations of markers can predict with high accuracy whether an individual will respond to active vaccination and become protected against recurring diseases.

The present invention relates to a method for determining cancer, the method comprising the steps of: measuring free PD-L1 (Programmed cell death-ligand 1) and free PD-1 (Programmed cell death-1) as free protein markers in a liquid sample collected from a subject, and determining whether or not the liquid sample is a sample collected from a subject suffering from cancer, based on measurement results.

Methods of treating cancer and improving immunotherapies comprising decreasing soluble immune receptor levels are provided. Agents that bind membranal immune receptor and inhibit proteolytic cleavage of the receptor and agents that bind soluble immune receptor and that are neither receptor agonists nor antagonists are also provided, as are methods of producing these agents.

The present disclosure relates generally to the analysis of immune checkpoint proteins involved in cancer. In particular, the present disclosure provides material and methods for determining abundance ratios of various immune checkpoint proteins (e.g., PD-1, PD-L1, and PD-L2) present in a biospecimen sample based on quantification of peak area using mass spectrometry analysis. The methods disclosed herein provide an alternative platform for diagnosing and treating cancer, especially in cases limited by ineffective antibody recognition.

Described herein are biomarkers comprising mTOR, PI3K/AKT, and MAPK/ERK signaling pathway members as well as cap-dependent translation initiation factors that enable monitoring and predicting responses to PD-1 pathway blockade in patients afflicted with cancers characterized by PD-1 expression.

The present invention relates to novel muteins derived from human tear lipocalin. The invention also refers to a corresponding nucleic acid molecule encoding such a mutein and to a method for its generation. The invention further refers to a method for producing such a mutein. Finally, the invention is directed to a pharmaceutical composition comprising such a lipocalin mutein as well as to various uses of the mutein.

Provided are methods and compositions for a combination therapy for liver disorders such as hepatocellular carcinoma. Also provided is a method for determining the effectiveness of therapy involving tyrosine kinase inhibitors such as sorafenib. The method comprises determining the status of PD-1 on T cells, and based on a change in the level of PD-1 on certain cells, a determination of the effectiveness of the tyrosine kinase, and an indication for a combination therapy comprising a lower dose of tyrosine kinase inhibitor and a PD-1 inhibitor can be made.

Methods for obtaining a tuberculosis assessment in a subject are provided. Aspects of the methods include assaying a tuberculosis (TB) activated sample from the subject for at least one of: (i) CD154.sup.+ T cells; and (ii) T cells having a central memory phenotype, such as a CM1 phenotype, CM2 phenotype or a CM3 phenotype; to obtain a TB biomarker signature, and then deriving a tuberculosis assessment for the subject from the TB biomarker signature. Aspects of the invention further include reagents, devices, systems, and kits thereof that find use in practicing the subject methods are provided. The methods and compositions find use in a variety of applications, including TB diagnosis and monitoring of TB treatment.

An object of the present invention is to provide an effective method of predicting an effect of treatment by a PD-1/PD-L1 blockade, which is a method of predicting whether or not PD-1/PD-L1 blockade is effective for treatment of a subject suffering from a malignant tumor, which comprises detecting abnormality of genome relating to effectiveness of the PD-1/PD-L1 blockade in a tumor cell taken from the subject and evaluating the PD-1/PD-L1 blockade as useful for the treatment of the subject when there is the abnormality.

Aspects of the disclosure relate to PD-1 binding proteins comprising immunoglobulin domains which bind specifically to PD-1 and comprise at least three or six specific complementarity determining regions (CDRs) and which comprise a specific feature in a variable domain framework region(s), e.g., heavy variable domain framework 1, heavy domain framework 4, and/or light chain variable domain framework 3 region(s). In some embodiments, the PD-1 protein comprises the substitution(s) L 108G and/or THOR of the heavy chain reference sequence and/or 158R relative to the light chain reference sequence(s). The PD-1 binding proteins are useful, e.g., as immunologic adjuvants, for detecting and quantifying PD-1, monitoring patient responses to therapies, diagnosing PD-1 related conditions, and treating or preventing disorders involving PD-1 expressing cells, such as, e.g., cancers and autoimmune diseases. Also provided herein are antigen binding proteins comprising amino acid substitutions in the heavy chain framework 4 region for improved stability and solubility.