Memorial Sloan Kettering Cancer Center

Ludwig Institute for Cancer Research Limited

Agenus Inc.

Icahn School of Medicine at Mount Sinai

Other

Sloan-kettering Institute for Cancer Research

Sloan-kettering Inststute for Cancer Research and the Animal Medical Center

The Simons Center for Systems Biology at the Institute for Advanced Study

Alphavax, Incorporated

Laessig, Michael

Jedd David Wolchok

Taha Merghoub

Stewart Shuman

Liang Deng

Gerd J Ritter

Marc A Van Dijk

Nicholas Stuart Wilson

David Schaer

Weiyi Wang

Peihong Dai

David Adam Savitsky

Cornelia Anne Mundt

Ning Yang

Dennis John Underwood

Roberta Zappasodi

Mark Arthur Findeis

Jean-Marie Cuillerot

Igor Proscurshim

Olga Shebanova

Takemasa Tsuji

Volker Seibert

Olivier Léger

Ana M Gonzalez

Peter M Palese

Adolfo Garcia-Sastre

Alan N Houghton

Dmitriy Zamarin

Rikke Baek Holmgaard

Rikke Bæk Holmgaard

David A Scheinberg

Arnold J Levine

Eric G Pamer

Timothy A Chan

Robert A Olmsted

Maureen Maughan

Yi Wang

Marta Luksza

Vinod P Balachandran

Benjamin D Greenbaum

Maria Lia Palomba

Steven D Leach

Michael Laessig

Gregory Mazo

Philip J Bergman

Wendy K Roberts

Krista Dubin

Alexander M Lesokhin

Francesca Avogadri

Marc Van Dijk

Eric Pamer

Volker Siebert

Olivier Leger

Nicolas S Wilson

The present disclosure relates to modified vaccinia Ankara (MVA) virus or MVAΔE3L delivered intratumorally or systemically as an anticancer immunotherapeutic agent, alone, or in combination with one or more immune checkpoint blocking agents for the treatment of malignant solid tumors. Particular embodiments relate to mobilizing the host's immune system to mount an immune response against the tumor.

Use of MVA or MVADELTAE3L as immunotherapeutic agents against solid tumors

Systems and methods for determining the likely responsiveness of a human cancer subject to a checkpoint blockade immunotherapy regimen are provided. Sequencing reads are obtained from samples from the subject representative of the cancer. A human leukocyte antigen type and a plurality of clones is determined from the sequencing reads. For each clone, an initial frequency Xin the one or more samples is determined and a corresponding clone fitness score of the clone is computed, thereby computing clone fitness scores. Each such fitness score is computed by identifying neoantigens in the respective clone, computing a recognition potential for each neoantigen, and determining the corresponding clone fitness score of the respective clone as an aggregate of these recognition potentials. A total fitness, quantifying the likely responsiveness of the subject to the regimen, is computed by summing the clone fitness scores across the plurality of clones.

Neoantigens and uses thereof for treating cancer

Disclosed herein are methods and compositions related to the treatment, prevention, and/or amelioration of cancer in a subject in need thereof. In particular aspects, the present technology relates to the use of genetically engineered or recombinant poxviruses, including a modified vaccinia Ankara (MVA) virus comprising a deletion of E3L (MVAΔE3L) engineered to express OX40L (MVAΔE3L-OX40L), an MVA virus comprising a deletion of C7L (MVAΔC7L) engineered to express OX40L (MVAΔC7L-OX40L), a MVAΔC7L engineered to express OX40L and human Fms-like tyrosine kinase 3 ligand (hFlt3L) (MVAΔC7L-hFlt3L-OX40L), an MVA comprising a deletion of E5R (MVAΔE5R), a vaccinia virus comprising a deletion of C7L (VACVΔC7L) engineered to express OX40L (VACVΔC7L-OX40L), a VACVΔC7L engineered to express both OX40L and hFlt3L (VACVΔC7L-hFlt3L-OX40L), a VACV comprising a deletion of E5R (VACVΔE5R), a myxoma virus (MYXV) comprising a deletion of M31R (MYXVΔM31R), or combinations thereof, alone or in combination with other agents, as an oncolytic and immunotherapeutic composition.

Recombinant poxviruses for cancer immunotherapy

The instant disclosure provides antibodies that specifically bind to CTLA-4 (e.g., human CTLA-4) and antagonize CTLA-4 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

Anti-CTLA-4 antibodies and methods of use thereof

Described herein are chimeric Newcastle disease viruses comprising a packaged genome comprising a transgene encoding interleukin-12. The chimeric Newcastle disease viruses and compositions thereof are useful in combination with an antagonist of programmed cell death protein 1 ('PD-1') or a ligand thereof in the treatment of cancer. In particular, described herein are methods for treating cancer comprising administering the chimeric Newcastle disease viruses in combination with an antagonist of PD-1 or a ligand thereof, wherein the chimeric Newcastle disease virus comprises a packaged genome comprising a transgene encoding interleukin-12.

Newcastle disease viruses and uses thereof

The present disclosure relates generally to the fields of oncology, virology and immunotherapy. It concerns poxviruses, specifically the highly attenuated modified vaccinia virus Ankara (MVA), and a recombinant modified vaccinia Ankara virus with deletion of vaccinia virulence factor E3 (MVAΔE3L), each further modified to express human Fms-like tyrosine kinase 3 ligand (Flt3L) or GM-CSF. The disclosure relates to use of the foregoing recombinant viruses as cancer immunotherapeutic agents. The foregoing recombinant poxviruses can also be used in combination with immune checkpoint blockade therapy.

Recombinant MVA or MVADELE3L expressing human FLT3L and use thereof as immuno-therapeutic agents against solid tumors

Provided are antibodies that specifically bind to CTLA-4 and/or PD-1 and antagonize CTLA-4 and/or PD-1 function. Also provided are pharmaceutical compositions and kits comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies either alone or in combination.

Antibodies and methods of use thereof

The present invention relates generally to the fields of oncology, virology and immunotherapy. More particularly, it concerns the use of poxviruses, specifically the replication competent attenuated vaccinia virus with deletion of thymidine kinase (VC-TK) with and without the expression of human Flt3L or GM-CSF as oncolytic and immunotherapy. The foregoing poxviruses can also be used in combination with immune checkpoint blocking agents. The foregoing poxviruses can also be inactivated via Heat or UV-treatment and the inactivated virus can be used as immunotherapy either alone or in combination with immune checkpoint blocking agents.

Replication competent attenuated vaccinia viruses with deletion of thymidine kinase with and without the expression of human Flt3L or GM-CSF for cancer immunotherapy

Disclosed herein are methods and compositions related to the treatment, prevention, and/or amelioration of cancer in a subject in need thereof. In particular aspects, the present technology relates to the use of poxviruses, including a recombinant modified vaccinia Ankara (MVA) virus or vaccinia virus with deletion of vaccinia host-range factor C7 (MVAΔC7L and VACVΔC7L, respectively), alone or in combination with immune checkpoint blocking agents, as an oncolytic and immunotherapeutic composition. In some embodiments, the technology of the present disclosure relates to a MVAΔC7L or VACVΔC7L virus further modified to express human Fms-like tyrosine kinase 3 ligand (Flt3L).

Vaccinia virus mutants useful for cancer immunotherapy

The present disclosure relates to infection-competent, but nonreplicative inactivated modified vaccinia Ankara (MVA) and its use as immunotherapy, alone, or in combination with immune checkpoint blocking agents for the treatment of malignant solid tumors. Particular embodiments relate to inducing an immune response in a subject diagnosed with a solid malignant tumor.

Use of inactivated nonreplicating modified vaccinia virus Ankara (MVA) as monoimmunotherapy or in combination with immune checkpoint blocking agents for solid tumors

The present disclosure provides antibodies that specifically bind to human glucocorticoid-induced TNFR family related receptor (GITR) and compositions comprising such antibodies. In a specific aspect, the antibodies specifically bind to human GITR and modulate GITR activity, e.g., enhance, activate or induce GITR activity, utilizing such antibodies. The present disclosure also provides methods for treating disorders, such as cancer and infectious diseases, by administering an antibody that specifically binds to human GITR and modulates GITR activity e.g., enhances, activates or induces GITR activity.

Anti-GITR antibodies and methods of use thereof

The instant disclosure provides antibodies that specifically bind to human PD-1 and antagonize PD-1 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

Anti-PD-1 antibodies and methods of use thereof

The present invention relates generally to the fields of oncology, virology and immunotherapy. More particularly, it concerns the use of a recombinant modified vaccinia Ankara (MVA) virus comprising an MVA harboring a human Fms-like tyrosine kinase 3 ligand (hFlt3L) (MVA-hFtl3L). The foregoing vaccinia Ankara (MVA) virus can be delivered to tumor cells of a subject afflicted with a malignant solid tumor, to treat the tumor. In a related aspect, the present disclosure concerns a recombinant modified vaccinia Ankara virus with deletion of vaccinia virulence factor E3 (MV At.E3L) modified to express human Fms-like 5 tyrosine kinase 3 ligand (hFlt3L) isolated, suitable for use as an immunotherapeutic agent against a malignant solid tumor.

Recombinant MVA or MVA&#x394;E3L expressing human FLT3L and use thereof as immuno-therapeutic agents against solid tumors

Growing community of inventors

New York, NY, United States of America

Jedd David Wolchok