The General Hospital Corporation

The Broad Institute, Inc.

Dana-farber-cancer Institute Inc.

Massachusetts Institute of Technology

Whitehead Institute for Biomedical Research

Biontech US Inc.

Leland Stanford Junior University

The Scripps Research Institute

Mount Sinai School of Medicine

Sanofi Pasteur Vaxdesign Corporation

Vaxdesign Corporation

The General Hospital Corporation D/b/a Massachusetts General Hospital

Nir Hacohen

Michael Steven Rooney

Edward F Fritsch

Catherine J Wu

Glenn Dranoff

Kai W Wucherpfennig

Harvey I Cantor

Catherine Ju-Ying Wu

Donald Raymond Shaffer

Penghui Zhou

Diana Alvarez Arias

Darrell J Irvine

Aviv Regev

Paul Blainey

William L Warren

Russell Higbee

Heather Fahlenkamp

Guzman Sanchez-Schmitz

Anatoly Kachurin

Robert Parkhill

Conan Li

Mike Nguyen

Gwendalyn J Randolph

Bruce Torbett

Jennifer Grace Abelin

Dominik Barthelme

Rob Carl Oslund

Moshe Sade-Feldman

Ute E Burkhardt

Dwayne Vickers

Peter H Seeberger

Sachet Ashok Shukla

Rahul Satija

Gad Getz

Oren Parnas

Eddie Adams

Alexandra-Chloé Villani

Pavan Bachireddy

Mark A Krasnow

Jing Sun

Yuk Yuen Lan

Siranush Sarkizova

Keren Yizhak

Matthew Bakalar

Marko Jovanovic

Marciela Degrace

Sagi Shapira

Liguo Wu

Thomas Eisenhaure

Mark Nackyoung Lee

Michael S Roonery

The present disclosure relates to methods for profiling subject specific and personalized T cell receptor (TCR) repertoires using a single-cell sequencing method. More particularly, disclosed are methods for determining binding of T cell receptors to subject specific neoantigens. In addition, the techniques herein may identify the antigenic targets of T cell receptors in the context of tumor neoantigens. Moreover, the present disclosure enables the discovery of T cell targets in numerous diseases, with implications for understanding the basic mechanisms of the mammalian immune response and for developing antigen-specific diagnostic markers and therapies. Finally, cloned TCRs can be used to formulate personalized immunotherapies for those inflicted with a disease, such as cancer.

Methods for profiling the T-cell-receptor repertoire

The present invention discloses a method for predicting peptides that are capable of binding to HLA molecules that incorporate the crystal structure of HLA molecules. An improved HLA-specific peptide docking workflow is used to simulate the occupancy of a peptide on the binding pocket of an HLA molecule, and three models are trained to predict the binding of the peptide to HLA molecules. The results show that these models predict HLA-allele specific binding peptides with extremely high accuracy.

Method for predicting HLA-binding peptides using protein structural features

The subject matter disclosed herein is generally directed to CD8+ tumor infiltrating lymphocytes comprising gene signatures associated with response to immunotherapy treatment. Moreover, the subject matter disclosed herein is generally directed to methods and compositions for use of the gene signatures. Specifically, disclosed herein are gene signatures associated with response to checkpoint blockade therapy and immune cell subtypes characterized by said gene signatures. Further disclosed are methods of using said gene signatures and immune cell subtypes. Further disclosed are pharmaceutical compositions comprising populations of CD8+ TILs enriched for a specific subtype.

Methods and compositions of use of CD8+ tumor infiltrating lymphocyte subtypes and gene signatures thereof

A system and method for isolating target substrates includes a microfluidic chip, comprising a plurality of processing units, each processing unit comprising: an inlet port, a plurality of first chambers connected to the inlet port by a fluid channel, the fluid channel comprising a plurality of valves, a plurality of second chambers, each of the second chambers connected to a respective first chamber by a fluid channel, each fluid channel including a controllable blocking valve, and a plurality of respective outlet ports, each outlet port in fluid communication with a respective one of said second chambers and each outlet port including a blocking valve. A magnet is adjacent the microfluidic chip and is movable relative to the microfluidic chip. A valve control is capable of actuating certain ones of the controllable blocking valves in response to a control signal.

Multi-stage, multiplexed target isolation and processing from heterogeneous populations

Systems, compositions, and methods for isolating HLA-peptides from cells. A universal platform and methods for profiling the HLA-peptidome, enabling identification of endogenously presented HLA-peptides from cell lines expressing any possible class I or II construct.

HLA-based methods and compositions and uses thereof

In one aspect, provided herein is a method comprising: (a) (i) determining cytolytic activity in a tumor from the subject; and/or (ii) determining genetic alterations associated with cytolytic activity in the tumor; and (b) administering an immunotherapeutic agent to the subject if (i) cytolytic activity is detected in the tumor and/or (ii) a genetic alteration associated with induction of cytolytic activity, tumor resistance to cytolytic activity and/or suppression of cytolytic activity is detected in the tumor.

Molecular biomarkers for cancer immunotherapy

Provided herein, in some embodiments, are methods for treating age-associated conditions, including systemic inflammation and disease, via enhanced DNA degradation.

Treatment of aging-associated conditions by DNA degradation

Compositions and methods for isolating HLA-peptides from cells. A universal platform and methods for profiling the HLA-peptidome, enabling identification of endogenously presented HLA-peptides from cell lines expressing any possible class I or II construct.

Provided herein are methods of determining resistance to checkpoint blockade (CPB) therapy in a cancer patient, methods of typing tumor cells of a cancer patient, methods of assigning treatment to a cancer patient and methods of treatment of a cancer patient based on determining in a tumor sample of said patient, reduced expression of a gene relating to antigen processing pathway or a product thereof, or a modification causing said reduced expression, wherein the presence of said reduced expression or modification is indicative of resistance to CPB therapy.

Resistance to checkpoint blockade therapy

The present invention provides isolated immune cells, immune cell populations and compositions, as well as markers, marker signatures and molecular targets characterising the immune cells. The cell products, substances, compositions, markers, marker signatures, molecular targets, kits of parts and methods of the present invention provide for new ways to characterise, evaluate and modulate the immune system and immune responses.

Product and methods useful for modulating and evaluating immune responses

The present disclosure provides, in part, methods of discovering immunotherapy targets in vivo, therapeutic compositions (e.g., shRNA, immunoresponsive cells expressing shRNA and/or a chimeric antigen receptors (CAR)), and methods of use thereof.

Methods and compositions for reducing immunosuppression by tumor cells

The present invention relates to neoplasia vaccine or immunogenic composition administered in combination with other agents, such as checkpoint blockade inhibitors for the treatment or prevention of neoplasia in a subject.

Combination therapy with neoantigen vaccine

The invention involves a method for modulating leukocyte activity, comprising delivering to a leukocyte a vector containing nucleic acid molecule(s), whereby the leukocyte contains Cas9 and the vector expresses one or more RNAs to guide the Cas9 to introduce mutations in one or more target genetic loci in the leukocyte, thereby modulating expression of one or more genes expressed in the leukocyte. The invention also involves identifying genes associated with leukocyte responses and experimental modeling of aberrant leukocyte activation and diseases associated with leukocytes by introducing mutations into leukocytes. The invention comprehends testing putative treatments with such models, e.g., testing putative chemical compounds that may be pharmaceutically relevant for treatment or gene therapy that may be relevant for treatment, or combinations thereof. The invention allows for the study of genetic diseases and putative treatments to better understand and alleviate leukocyte associated diseases.

Delivery, use and therapeutic applications of the CRISPR-cas systems and compositions for modeling mutations in leukocytes

Methods for profiling the t cell repertoire

Growing community of inventors

Brookline, MA, United States of America

Nir Hacohen