Combination tumor immunotherapy

Abstract

Provided are methods for treating cancer using local administration of certain CpG oligonucleotides (CpG ODN) and systemic administration of a checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, and / or an anti-CLA-4 antibody. In preferred embodiments, the CpG ODN are selected based on their propensity to induce high amounts of interferon alpha (IFN-α) and T-cell activation relative to interleukin-10 (IL-10) and B-cell activation. In certain embodiments, the methods further include pretreatment with radiotherapy, to potentiate the combination immunotherapy.

Description

RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Patent Application No. 62 / 098,568, filed Dec. 31, 2014; United States Provisional Patent Application No. 62 / 106,526, filed Jan. 22, 2015; and U.S. Provisional Patent Application No. 62 / 118,165, filed Feb. 19, 2015.BACKGROUND OF THE INVENTION[0002]Many scientists have sought to treat cancer by activating the immune system against the tumor. However, despite occasional successes, durable responses to immune therapy have been rare and limited to just a few tumor types. Current understanding of cancer immunotherapy among those skilled in the art has been summarized in recent review articles, including for example Chen and Mellman, Immunity 2013 39(1): 1-10. The cycle for induction of therapeutic immune responses against tumors may be broken down into seven distinct steps (FIG. 1):[0003]1. Release of cancer cell antigens;[0004]2. Presentation of cancer cell antigens by antigen-presenting cells (APC, usually ...

AI Technical Summary

Benefits of technology

[0019]The present invention also is based, at least in part, on the finding that delivery of the CpG ODN into tumors (directly or indirectly) induces the expression of adhesion molecules in the local vasculature in and around the tumor, and promotes the egress of activated T cells (CD4+ and CD8+) from capillaries into the tumor and surrounding region. Some of these T cells will be specific to the unmutated and mutated tumor-associated antigens (TAA). In the absence of checkpoint inhibitors and / or XRT, these T cells may be inhibited by the tumor, but in combination, this creates a much more powerful anti-tumor effect than can be achieved with CpG or the checkpoint inhibitors or XRT on their own.

Problems solved by technology

However, despite occasional successes, durable responses to immune therapy have been rare and limited to just a few tumor types.

The art does not teach designs of TLR9 agonists that have improved anti-tumor effects as a result of inducing lower amounts of IL-10 production.

Nevertheless, this increasing recent understanding of the cycle of tumor immunity has heightened awareness that it may be possible to increase the clinical efficacy of cancer immunotherapy by using combinations of agents that act at different points in this cycle for induction of therapeutic immune responses against tumors, but the art does not provide a deep enough understanding of the immunobiology of cancer to predict which of the many different possible combinations will be preferred.

Systemic administration of anti-CTLA-4 antibodies has led to durable responses in ˜10% of patients with melanoma, and some encouraging early results in other tumor types, but at the cost of a high rate of adverse effects, including death in some patients.

Aside from melanoma, in which pre-existing anti-tumor immunity is relatively common, TIL are relatively uncommon in most other tumor types, indicating that CPI may be of limited benefit in most types of cancer.

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