University of Pittsburgh

Kalivir Immunotherapeutics, Inc.

Leland Stanford Junior University

Other

Kalivir Immunotherapeutcs, Inc.

Stephen Howard Thorne

Mingrui Zhang

Daniel J Byrd

Christopher H Contag

Jianghong Rao

David Francis Ackerley

Song Li

Greg M Delgoffe

A C Matin

Yoram Barak

Susan V Lynch

Padmavathi Sampath

Dayana Rivadeneira

The disclosure relates to modified oncolytic viruses. The modified oncolytic viruses of the disclosure comprise modification in the viral genome encoding exogenous nucleic acids to enhance the oncolytic immunotherapy by remodeling the tumor microenvironment and with enhanced systemic delivery. The disclosure further relates to compositions comprising the modified oncolytic viruses, kits containing the same, and methods of using the oncolytic viruses.

Oncolytic immunotherapy by tumor micro-environment remodeling

This disclosure provides a modified oncolytic virus that can contain modifications in the viral genome and exogenous nucleic acids coding for proteins. The modified oncolytic virus can be utilized as a platform vector for systemic delivery.

Platform oncolytic vector for systemic delivery

This disclosure relates to modified viruses, e.g., oncolytic vaccinia viruses, which have been modified to contain an exogenous nucleic acid that expresses a protein that modulates STAT3 activity. It is based, at least in part, on the discovery that vaccinia viruses modified to contain nucleic acid encoding PIAS3 and that express PIAS3 or a fragment thereof can inhibit STAT3 activity and enhance the anti-cancer activity of the vaccinia virus. Accordingly, this disclosure provides for oncolytic vaccinia viruses and methods of using them in the treatment of cancers.

Oncolytic viruses targeting STAT3

Described herein are modified oncolytic viruses that can contain modifications in the viral genome and exogenous nucleic acids coding for proteins. The modified oncolytic virus can be utilized as a platform vector for systemic delivery. Further described herein are oncolytic viruses having an exogenous nucleic acid that codes for a protein or a functional variant thereof that enhances degradation of an extracellular matrix (ECM) associated with a tumor, wherein the protein is a membrane associated protein.

A method of modifying a virus for in vivo delivery to a region of interest includes forming an enveloping composition including a lipid conjugate formed by conjugating at least one lipid with at least one hydrophilic compound via a linkage which is cleavable under conditions present in the region of interest and combining the virus with the enveloping composition to encompass the virus within the enveloping structure.

Synthetically enveloped virus

The present disclosure provides for recombinant oncolytic viruses with gene deletions or insertions which result in downregulation of Major Histocompatibility Complex class I and alternatively or additively upregulation of Major Histocompatibility Complex class II. Immunologic and pharmaceutical compositions comprising these recombinant viruses and methods of using these compositions are also presented.

Oncolytic viruses for modified MHC expression

Recombinant oncolytic viruses (OVs) that express one or more metabolic modulator proteins, such as an adipokine (e.g., leptin or chemerin), insulin, and/or IGF-1, and methods of their use to treat cancer, for example in immunotherapy anti-cancer treatments. In some examples, such recombinant OVs and methods increase T cell infiltration into the tumor or tumor microenvironment.

Expression of metabolic modulators in tumor microenvironment to improve tumor therapy

The present invention relates to oncolytic vaccinia viruses which have been modified to promote anti-tumor immunity and/or reduce host immunity and/or antibody response against the virus. It is based, at least in part, on the discovery that oncolytic vaccinia virus (i) bearing a genome deletion of a gene that reduces T cell immunity (interleukin-18 binding protein); (ii) treated with a sialidase enzyme which is believed to reduce TLR2 activation and therefore the antibody response; (iii) carrying a gene that enhances cytotoxic T lymphocyte induction (e.g., TRIF) and/or (iv) reduces tumor myeloid-derived suppressor cells by reducing prostaglandin E2 reduces tumor growth. Accordingly, the present invention provides for immunooncolytic vaccinia viruses and methods of using them in the treatment of cancers.

Immuno-oncolytic therapies

Provided herein are oncolytic vaccinia viruses which have been modified to contain an exogenous nucleic acid that codes for a variant HMGB1 protein. Such vaccinia viruses modified to contain nucleic acid encoding variant HMGB1 and that express a variant HMGB1 or a fragment thereof can achieve a synergistic effect in combination with chemotherapy. Methods of using oncolytic vaccinia viruses modified to contain an exogenous nucleic acid that codes for a variant HMGB1 protein, in the treatment of various cancers, are also provided.

High mobility group box I mutant

Compositions and methods are provided for the treatment of cancer. An immune effector cell population is pre-infected with an oncolytic virus. The combined therapeutic is safe and highly effective, producing an enhanced anti-tumor effect compared to either therapy alone. The methods of the invention thus provide for a synergistic effect based on the combined biotherapeutics.

Immune effector cells pre-infected with oncolytic virus

Compositions and methods are provided for the treatment of cancer.

Growing community of inventors

Pittsburgh, PA, United States of America

Stephen Howard Thorne