Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof

Abstract

Cancer biomarkers and methods of using them are disclosed.

Description

[0001]This application is a continuation of U.S. application Ser. No. 15 / 517,597, filed Apr. 7, 2017, now allowed, which is a U.S. national phase application under 35 U.S.C. § 371 of International Application No. PCT / US2015 / 054542, filed Oct. 7, 2015, which claims priority to U.S. Ser. No. 62 / 061,553 filed Oct. 8, 2014 and U.S. Ser. No. 62 / 144,682 filed Apr. 8, 2015, the contents of which are incorporated herein by reference in their entireties.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 7, 2015, is named N2067-7057WO_SL.txt and is 219,221 bytes in size.FIELD OF THE INVENTION[0003]The invention relates to cancer biomarkers and uses thereof.BACKGROUND OF THE INVENTION[0004]Many patients with B cell malignancies are incurable with standard therapy. In addition, traditional treatment options often have serious si...

AI Technical Summary

Benefits of technology

[0008]The present disclosure relates to the identification and use of analytes, analyte profiles, or markers (e.g., gene expression, flow cytometry and / or protein expression profiles) with clinical relevance to cancer (e.g., a hematological cancer such as chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL)). In some embodiments, the disclosure provides the identity of genes, whose expression, at the transcriptional and protein levels, are correlated with CLL and ALL progression, e.g., as a way of predicting a response to a Chimeric Antigen Receptor (CAR)-expressing cell therapy (e.g., a therapy comprising a cell (e.g., an immune effector cell or population of cells) that expresses a CAR that binds to CD19 (also referred to herein as a “CAR19” or “CD19 CAR”-expressing cell). In certain embodiments, one or more of a CD19 CAR-expressing cell gene set signature, a biomarker listed in Table 1A, Table 1B, Table 7A, Table 7B, Table 8, Table 9, Table 10, Table 14, Table 15, Table 16 (e.g., CCL20, IL-17a and / or IL-6), Table 17, Table 18, Table 20, a CD27 biomarker, a CD45RO biomarker, a PD-1 biomarker, a LAG-3 biomarker, a TIM-3 biomarker, an IL2RA biomarker, an IL21 biomarker, a CD4 biomarker, a CD8 biomarker, a TH1+ helper T cell gene set signature, a TH2+ helper T cell gene set signature, a memory T cell (e.g., a CD8+ memory T cell, e.g., a naïve T cell (TN), e.g. a memory stem cell (TSCM), e.g. a central memory T cell (TCM), e.g. an effector memory T cell (TEM)) gene set signature, and combinations thereof) are evaluated. These gene expression profiles may be applied to the diagnosis and / or prognosis of a cancer, e.g., a hematological cancer such as CLL and ALL, and are particularly useful in predicting whether a subject will respond favorably to a CAR therapy (e.g., a CD19 CAR therapy as described here, e.g., a CTL019 therapy) in a subject diagnosed with a cancer, e.g., a hematological cancer such as CLL or ALL. Compared to clinical parameters or biochemical markers used in existing prognosis methods, the expression profiles of the genes disclosed herein constitute a more robust signature of hematological cancer progression (e.g., CLL and ALL progression) and provide a more reliable, non-subjective basis for the selection of appropriate therapeutic regimens.

Problems solved by technology

In addition, traditional treatment options often have serious side effects.

Attempts have been made in cancer immunotherapy, however, several obstacles render the goal of clinical effectiveness difficult to achieve.

Although hundreds of so-called tumor antigens have been identified, these are generally derived from self and thus are poorly immunogenic.

Furthermore, tumors use several mechanisms to render themselves hostile to the initiation and propagation of immune attack.

Images