Immunomodulatory Oncolytic Adenoviral Vectors, and Methods of Production and Use Thereof for Treatment of Cancer

Abstract

Disclosed herein are compositions and methods for treating cancer in a subject. This involves administering an oncolytic virus containing a heterologous DNA sequence encoding one or more immunomodulatory and / or immunostimulatory polypeptide(s) of interest to the subject under conditions effective to enhance an anti-tumor immune response in the subject, and to treat cancer. It also relates to a method of enhancing the delivery to and distribution within a tumor mass of therapeutic viruses.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of co-pending U.S. application Ser. No. 15 / 834,690, filed Dec. 7, 2017, which claims the benefit of U.S. Provisional Application Nos. 62 / 572,206, filed Oct. 13, 2017; 62 / 440,646, filed Dec. 30, 2016; and 62 / 440,670, filed Dec. 30, 2016, each of which is incorporated herein by reference in its entirety.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 Dec. 21, 2017, is named 42022US_CRF_sequencelisting.txt and is 266,186 bytes in size.FIELD[0003]The invention described herein relates generally to the fields of immunology, virology, molecular biology, and more specifically to oncolytic adenoviruses having therapeutic applications.BACKGROUND[0004]Cancer is a leading cause of death in the United States and elsewhere. Depending on the type of canc...

AI Technical Summary

Problems solved by technology

These treatments often fail, and it is clear that new therapies are necessary, to be used alone or in combination with current standards of care.

Several attempts to achieve tumor-selective control through the insertion of tumor selective promoter elements upstream of the E1 or other adenovirus critical promoters have had variable levels of success, but ultimately were limited by “leaky” gene expression of viral proteins in non-tumor cells and by reduced ability to propagate and lyse tumor cells compared to wild-type virus infections.

In some embodiments, the treatment / therapy that a subject receives does not cure cancer, but prevents the progression or worsening of the disease.

In certain embodiments, the treatment / therapy that a subject receives does not prevent the onset / development of cancer, but may prevent the onset of cancer symptoms.

This results in high levels of transgene expression that are specifically expressed during periods of viral replication, as the E3 promoter only becomes transcriptionally active during these times. Using a modified adenovirus backbone, such as the E1a enhancer modification described herein, to limit viral replication to infected tumor cells, expression from the introduced transgene is also limited to infected tumor cells and, generally, not normal cells.

Such inhibitory cytokines decrease T effector cell function.

Treatment-related weight loss in excess of 20% is generally considered unacceptably toxic.

Images