Methods and compositions for treating cancer

A composition, technology of cancer, applied in the fields of molecular biology and medicine

Pending Publication Date: 2021-11-12
BOARD OF RGT THE UNIV OF TEXAS SYST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the various regimens of immunotherapy, the combination of anti-CTLA-4 and anti-PD-1 provided superior response rates compared to administration of the same agents as monotherapy, however, this was offset by a higher risk of severe toxicity offset
High frequency of severe to life-threatening toxicities with anti-CTLA-4 and anti-PD-1 combination therapy has been a limiting factor for clinicians to prescribe this form of treatment
[0006] Although some factors have been identified that correlate with patient response to immune checkpoint blockade therapy, there remains a need in the art for the prediction of toxicity due to immune checkpoint blockade therapy and the identification of responders to immune checkpoint blockade combination therapy. predict

Method used

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  • Methods and compositions for treating cancer
  • Methods and compositions for treating cancer
  • Methods and compositions for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0250] Example 1 - Molecular, immune and microbial factors in response and toxicity to combined CTLA-4 and PD-1 blockade

[0251] Cancer treatment paradigms are rapidly evolving, driven by parallel advances in the ability to understand and deeply characterize tumors at the genomic and immune levels. Checkpoint blockade immunotherapy targeting negative regulatory pathways that lead to ineffective antitumor immune responses in patients is now a practical and effective strategy in widespread clinical use. A variety of new agents are in development, designed to block immunosuppressive or activate immunostimulatory molecular targets. Efforts to improve response rates to checkpoint blockade are currently dominated by combination drug strategies, exemplified by the combination of CTLA-4 and PD-1 inhibitors (Combined Immune Checkpoint Blockade, CICB). Although more effective at inducing objective responses (Larkin et al., 2015), this combination was associated with significant immune...

Embodiment 2

[0346] Example 2: Efficacy and tolerability of combined immune checkpoint blockade in metastatic melanoma is influenced by the gut microbiome

[0347] The gut microbiome is increasingly recognized as a powerful modulator of anti-PD1-based cancer immunotherapy. Compelling evidence for differential bacterial enrichment and diversity in responders (R) versus non-responders (NR) is mediated by profound effects on systemic and antitumor immune infiltrates. However, this has not been studied in the context of treatment with combined immune checkpoint blockade (CICB), which is associated with excellent response rates but a higher incidence of potentially debilitating toxicities. Methods: The inventors recruited a cohort of metastatic melanoma patients (n=54) who were undergoing CICB. All patients were classified as R (n=31, CR+PR) or NR (n=23, SD+PD) based on RECIST v1.1 and as having grade 3 or higher according to NCI CTCAE 4.0 criteria Grade (T; n=29) or less than grade 3 (NT; n=...

Embodiment 3

[0349] Example 3: Peripheral immune repertoire and gut microbiome signatures correlate with toxicity against combined blockade of CTLA-4 and PD-1

[0350] Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit in several tumor types, but also with a high incidence of immune-related adverse events (irAEs). A better understanding of biomarkers and mechanisms of response and toxicity against CICB is needed. To address this question, the inventors analyzed the blood, tumor, and gut microbiomes of 77 advanced melanoma patients treated with CICB, and the incidence of any grade ≥3 irAEs was high (49%). Immune and genomic biomarkers of response to CICB were similar to those identified for anti-CTLA-4 and anti-PD-1 monotherapy. Toxicity from CICB was associated with a more diverse T-cell repertoire and a less antigen-stimulated phenotype. Novel microbial determinants of toxicity against CICB, such as Bacteroidetes enter...

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Abstract

Described herein are methods and compositions for treating cancer and for predicting a subjects' response to combination checkpoint inhibitor therapy. Aspects of the disclosure relate to a method of treating cancer and / or reducing toxicity to a therapy in a subject comprising administering to the subject a composition comprising at least one isolated or purified population of bacteria belonging to one or more of the genera Flavonifractor, Dielma, Akkermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzzerella, Parabacteroides distasonis, Fournierella, Fournierella massiliensis, Eisenbergiella tayi, Tissierellales, Hungateiclostridium thermocellum, Dorea formicigenerans, Caloramator coolhaasi, Muricomes, Geosporobacter, Prevotella paludivivens, Lactobacillus secaliphilus, Bacteroides fmegoldii, Lactobacillus johnsonii, Parapedobacter composti, and Anaerotignum lactatifermentans and wherein the method further comprises treating the subject with a combination of (i) a PD-1, PDL1, or PDL2 inhibitor and (ii) a CTLA-4, B7-1, or B7-2 inhibitor.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 770603, filed November 21, 2018, and U.S. Provisional Patent Application No. 62 / 826631, filed March 29, 2019, which are incorporated herein by reference in their entirety . [0003] Background of the invention technical field [0004] The present invention relates to the fields of molecular biology and medicine. Background technique [0005] Cancer treatment has made enormous strides in the past decade through the use of targeted therapies and immunotherapies. By blocking immunosuppressive ligand-receptor interactions involving CTLA-4 and PD-1, checkpoint blockade immunotherapy attenuates a major inhibitory signal in T lymphocytes, thereby enhancing potential T cell-mediated antitumor effects immune activity. However, general attenuation of systemic inhibitory signaling also activates T lymphocytes reactive to self-anti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/742A61K35/747A61K35/74A61P35/00C12Q1/689
CPCC12Q1/689C12Q2600/106A61K35/74A61K35/747A61K35/742A61P35/00A61K35/741A61K39/3955A61K2039/505
Inventor 詹尼弗·A·沃戈万切斯瓦兰·戈帕拉克里希南迈尔斯·C·安德鲁斯劳伦斯·齐特福格尔瓦莱里奥·耶巴
Owner BOARD OF RGT THE UNIV OF TEXAS SYST
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