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Smc combination therapy for treatment of cancer

A cancer, VSV-M51R technology, applied in the field of treatment of patients diagnosed with cancer, can solve problems such as insufficient treatment of cancer

Inactive Publication Date: 2018-11-23
东安大略儿童医院研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, SMCs alone may not be sufficient to treat some cancers

Method used

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  • Smc combination therapy for treatment of cancer
  • Smc combination therapy for treatment of cancer
  • Smc combination therapy for treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0224] Example 1: Smac Mimetics Trigger Tumor Destruction by the Innate Immune System

[0225] Smac mimetic compounds, a class of apoptosis-sensitizing drugs, have been shown to be safe in phase I trials in cancer patients. Stimulation of the innate antipathogen response can generate an effective and safe inflammatory "cytokine storm" that triggers the death of tumors treated with Smac mimics. This example demonstrates the activation of innate immune responses by oncolytic viruses and adjuvants such as poly(I:C) and CpG to induce bystanders in cancer cells treated with Smac mimetics in a manner mediated by IFNβ, TNFα or TRAIL cell death. This therapeutic strategy can lead to durable cures, for example, in several mouse models of aggressive cancers. As these and other innate immune stimulants have been shown to be safe in human clinical trials, the data presented here strongly point to their use in combination with Smac mimetics for the treatment of cancer.

[0226] This exa...

Embodiment 2

[0254] Example 2: Inactivated Virus Particles, Cancer Vaccines and Stimulatory Cytokines Synergize with SMCs to Kill Tumors

[0255] Current cancer immunotherapies such as BCG (Bacillus Calmette-Guerin), recombinant interferons (eg IFNα) and recombinant tumor necrosis factor (eg TNFα for isolated limb perfusion), and more recently clinically used biologics ( The application of immune checkpoint inhibitors (such as anti-CTLA-4 and anti-PD-1 or PDL-1 monoclonal antibodies) to overcome tumor-mediated suppression of the immune system highlights "cancer immunotherapy" as an effective potential for therapeutic forms. As shown in Example 1, we have demonstrated the strong potential of non-viral immunostimulants to act synergistically with SMCs (Figure 5). To extend these studies, we also examined the potential of SMCs to synergize with non-replicating rhabdovirus-derived particles (termed NRRPs), which are UV-irradiated particles that retain their infectivity and immunostimulatory p...

Embodiment 3

[0305] Example 3: Immunotherapy containing SMC shows anti-myeloma activity

[0306] Immune checkpoint blockade synergizes with SMC therapy to delay disease progression in MM

[0307] MPC-11 cells stably expressing the luciferase transgene were implanted into BALB / c mice by intravenous injection. This in vivo MM model mimics human disease well and follows predictable disease progression. MPC-11 cells were obtained from murine plasmacytoma. After two rounds of treatment with SMCs and monoclonal antibodies against PD-1 or CTLA-4, only anti-PD-1-based therapy showed a response with delayed disease progression. Mice treated with the combination of anti-PD-1 and SMC showed the best response with little tumor burden as determined by luminescent signal (Figure 35). The combination also significantly prolonged the survival of mice compared to the control group (p=0.01), and compared to PD-1 treatment alone (p=0.0163).

[0308] Type 1 interferons cooperate with SMCs to cause MM cell...

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Abstract

The present invention includes methods and compositions for enhancing the efficacy of SMCs in treatment of cancer. In particular, the present invention includes methods and compositions for combination therapies that include an SMC and at least a second agent that stimulates one or more apoptotic or immune pathways. The second agent may be, e.g., an immunostimulatory or immunomodulatory compound or oncolytic virus.

Description

Background of the invention [0001] Cell death by apoptosis (or programmed cell death), and other cell death pathways are regulated by various cellular mechanisms. Inhibitor of apoptosis (IAP) proteins, such as X-linked IAP (XIAP) or cellular IAP proteins 1 and 2 (cIAP1 and 2), are regulators of programmed cell death, including (but not limited to) e.g. in cancer cells Apoptotic pathway. Other forms of cell death may include, but are not limited to, necroptosis, necrosis, pyroptosis, and immunogenic cell death. Furthermore, these IAPs regulate various cell signaling pathways through their ubiquitin E3 ligase activity, which may or may not be associated with cell survival. Another modulator of apoptosis is the polypeptide Smac. Smac is a pro-apoptotic protein released from mitochondria involved in cell death. Smac can bind to IAP and antagonize its function. Smac mimetic compounds (SMCs) are non-endogenous pro-apoptotic compounds capable of performing one or more functions ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K38/05A61K35/76A61K39/395A61K35/766A61K38/19A61K38/21A61P35/00
CPCA61P35/00A61K31/00A61K35/76A61K35/766A61K38/05A61K38/191A61K38/21A61K39/395A61K45/06A61K39/3955C07K16/2818A61K2300/00A61K31/433A61K31/426A61K31/427A61K31/198A61K31/437A61K31/407A61K31/4025A61K31/5377A61K31/409A61K31/41A61K47/55
Inventor R·G·科恩卢克E·C·拉卡斯S·T·博伊格V·A·唐
Owner 东安大略儿童医院研究所
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