Immune effector cells pre-infected with oncolytic virus

Abstract

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.

Description

[0001] This invention was made with Government support under contract P01 CA 49605-14 awarded by the National Cancer Institute. The Government has certain rights in this invention.BACKGROUND OF THE INVENTION [0002] Neoplasia is a process that occurs in cancer, by which the normal controlling mechanisms that regulate cell growth and differentiation are impaired, resulting in progressive growth. This impairment of control mechanisms allows a tumor to enlarge and occupy spaces in vital areas of the body. If the tumor invades surrounding tissue and is transported to distant sites it will likely result in death of the individual. [0003] The desired goal of cancer therapy is to kill cancer cells preferentially, without having a deleterious effect on normal cells. Several methods have been used in an attempt to reach this goal, including surgery, radiation therapy, and chemotherapy. [0004] Local treatments, such as radiation therapy and surgery, offer a way of reducing the tumor mass in re...

AI Technical Summary

Benefits of technology

[0012] Pre-infection of effector cells with oncolytic virus resulted in a prolonged eclipse period where the virus remained within the cells until interaction with, and infiltration into, the tumor. The infected cells are preferably administered to the patient during the eclipse phase. In the combined therapeutic, the effector cells were shown to retain their ability to traffic to tumors. At the tumor site the oncolytic virus was released deep in the tumor rather than merely at the surface; thus the cell mediated delivery of the virus led to enhanced biodistribution within the tumor. In addition, the cytotoxic effects of the effector cells may be increased by viral replication in the tumor target. This combined therapeutic has been demonstrated to be safe, with minimal viral infection of normal tissues, 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.

Problems solved by technology

This impairment of control mechanisms allows a tumor to enlarge and occupy spaces in vital areas of the body.

If the tumor invades surrounding tissue and is transported to distant sites it will likely result in death of the individual.

Moreover, these treatments are not applicable to the destruction of widely disseminated or circulating tumor cells eventually found in most cancer patients.

However, chemotherapeutic agents are limited in their effectiveness for treating many cancer types, including many common solid tumors.

This failure is in part due to the intrinsic or acquired drug resistance of many tumor cells.

Another drawback to the use of chemotherapeutic agents is their severe side effects.

A major limitation of this approach is that these replication-incompetent viruses require a helper virus to be able to integrate and / or replicate in a host cell.

These viruses are limited in their effectiveness, because each replication-defective retrovirus particle can enter only a single cell and cannot productively infect others thereafter.

Therefore, they cannot spread far from the producer cell, and are unable to completely penetrate many tumors in vivo.

However, while the virus-based approach has provided evidence of significant therapeutic effects in animal models of tumors, the method is limited by the efficiency of viral infection; the requirement of a helper virus or producer cell line for some viral vectors; tumor cell heterogeneity for the cellular factor(s) complementing viral mutant growth for other viral vectors; and antiviral immune responses.

Targeted biological therapies hold tremendous potential for the treatment of cancers, yet their effective use has been limited by constraints on delivery and effective tumor targeting.

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