University of California

California Institute of Technology

Nektar Therapeutics

Antoni Ribas

Alexander Marson

Theodore Lee Roth

Cristina Puig Saus

Eric Shifrut

David Baltimore

Lili Yang

Pin Wang

James Economou

Jesse Zaretsky

James R Heath

Owen N Witte

Deborah H Charych

Caius G Radu

Gabriel A Kwong

Thomas G Graeber

Daniel Shin

Paul C Tumeh

Blanca Homet Moreno

Richard C Koya

Thinle Chodon

Roger S Lo

Willy Hugo

Lidia Robert

Nicolaos Palaskas

Jennifer Tsoi

Giulia Parisi

Angel Garcia-Diaz

Provided herein are methods and compositions for editing the genome of a human T cell. In some embodiments, a heterologous T cell receptor (TCR)-β chain and a heterologous TCR-α chain are inserted into exon 1 of a TCR subunit constant gene in the genome of the T cell.

Targeted replacement of endogenous T cell receptors

The current methods and compositions provide for a novel therapeutic method for treating patients diagnosed with melanoma, especially those that have become resistant to certain other therapies. Accordingly, certain aspects of the disclosure relate to a method for treating melanoma in a subject, the method comprising administering a composition comprising a ferroptosis-inducing agent or other dedifferentiated melanoma-targeting agent to the subject.

Methods and compositions for treating melanoma

Provided herein are methods and compositions for editing the genome of a human T cell. In some embodiments, a heterologous T cell receptor (TCR)-&#x3b2; chain and a heterologous TCR-&#x3b1; chain are inserted into exon 1 of a TCR subunit constant gene in the genome of the T cell.

Provided are methods and compositions directed towards the treatment of an individual having cancer by providing adoptive cell transfer therapy and administering to the individual a long-acting IL-2R&#x3b2;-biased agonist.

Immunotherapeutic treatment method using an interleukin-2 receptor beta-selective agonist in combination with adoptive cell transfer therapy

A method of analyzing a biological sample from a subject that has a tumor or cancer, comprising: determining, for target cells having a phenotype of interest spatial resolution of the target cells, density of the spatially resolved target cells in the sample; and proximity between spatially resolved target cells of interest in the sample; and determining an overall score based at least in part on the preceding parameters. A method for identifying a patient as a responder to single agent anti-PD-1 or anti-PD-L1 therapy is provided. Similar methods are provided for detecting adaptive immune resistance, the presence of cancer in a patient sample, determining efficacy of cancer therapy, and determining response to and monitoring the efficacy of cancer therapy.

Methods for stratifying non-responders to therapies that block PD1/PDL1 axis

Methods of predicting or detecting sensitivity to therapeutic effects of anti-PD-1 therapy in a patient suffering from melanoma, as well as for selecting somatic mutanomes and transcriptomes of melanoma biopsies. A tumor sample obtained from the patient is assayed for a measure of anti-PD-1 therapy sensitivity via, for example, whole transcriptome sequencing, antibody based protein quantifications, mass spectrometry based protein quantification, targeted mRNA sequencing, real-time RT-PCR, Sanger sequencing, targeted sequencing and/or whole exome/genome sequencing. Samples are selected that exhibit a higher first enrichment similarity score and/or a lower second enrichment similarity score, and/or at least one measure of sensitivity. A patient whose sample was selected herein as a candidate for anti-PD-1 therapy is thereby identified. The method of the invention can further comprise treating the patient with anti-PD-1 therapy, optionally in conjunction with combinatorial therapy.

Detection and treatment of anti-PD-1 therapy resistant metastatic melanomas

Disclosed herein are methods of treating or assessing cancer in a subject wherein it has been determined whether the cancer comprises a loss of function mutation or disruption in an immune pathway. The loss of function mutation or disruption can be in JAK1 or JAK2. The loss of function mutation or disruption can be in B2M. The methods can include administering an immune checkpoint therapy such as anti-PD1 or anti-PDL1. The methods can include administering an alternative therapy to an immune checkpoint therapy. In some aspects, the method includes determining whether the cancer comprises a loss of function mutation or disruption in an immune pathway.

Methods for immunotherapy-based treatment and assessment of cancer

The invention relates to methods and materials that can be used to product cytotoxic T cells that target cancer cells expressing the cancer-testis antigen NY ESO-1. Illustrative embodiments of the invention include peripheral blood stem cells transduced with a lentiviral vector that comprises a codon optimized TCR alpha and beta chain polypeptides specific for NY ESO-1. These gene-modified cells are useful, for example, in a hematopoietic stem cell transplantation setting to treat patients diagnosed with NY ESO-1 positive cancers.

Codon-optimized lentiviral vector for stem cell reprogramming

T-cell receptors that recognize MART-1 antigen are provided. The TCRs can be used, for example, to treat patients suffering from melanoma.

MART-1 T cell receptors

Polynucleotide-encoded capture agents for target detection and in particular modular polynucleotide-capture agents comprising a target binding component, a scaffold component and an encoding component formed by standardized molecular units that can be coupled and decoupled in a controlled fashion, and related compositions methods and systems.

Capture agents and related methods and systems for detecting and/or sorting targets

Growing community of inventors

Los Angeles, CA, United States of America

Antoni Ribas