330 Investigating the clinical safety, efficacy, and immune modulation of combined XL888 and pembrolizumab in metastatic gastrointestinal malignancies

BackgroundBoth pancreatic ductal adenocarcinoma (PDAC) and metastatic colorectal cancer (mCRC) have yet to widely benefit from T cell-targeted immunotherapy and have universally poor prognoses. Thus, enhancing the activity of immunotherapy is a high priority. Our laboratory recently reported that heat shock protein-90 (Hsp90) inhibition enhances the efficacy of PD-1 blockade in preclinical models of PDAC.1 Mechanistically, Hsp90 inhibitors can limit activation of cancer associated fibroblasts (CAF) and promote infiltration of T cells when combined with PD-1 blockade. Based on these data, we are conducting a Phase Ib/II clinical trial to evaluate the combination of XL888 (Hsp90 inhibitor) and pembrolizumab in patients with metastatic pancreatic and colorectal cancers. We hypothesize that this combination will be safe and elicit pronounced microenvironmental changes, leading to enhanced efficacy.MethodsDuring the phase II portion, PDAC or mCRC patients (n=16 each) were randomized to receive a three week lead in with either pembrolizumab or pembrolizumab and XL888. Paired biopsies were obtained at baseline and at week two on treatment. A comprehensive panel of immunologic correlatives studies is being conducted to examine treatment-induced alterations in the tumor microenvironment and peripheral blood.ResultsAs of August 23rd, 2020, paired liver biopsy specimens from sites of metastasis have been successfully obtained from a total of 15 patients (n=7 PDAC and n=8 mCRC). These specimens underwent single cell mass cytometry (CyTOF) analysis to assess immunophenotypic markers of T and myeloid cells. Using this approach, we have generated a comprehensive view of the immune landscape at baseline and following treatment. These data will be validated by immunohistochemical analysis of FFPE biopsy specimens obtained in parallel at the time of CyTOF analysis. In addition to these correlative studies, using immortalized and primary CAF from PDAC patients, we have shown XL888 dampens production of IL-6 and other cytokines in vitro. The impact of XL888 on systemic cytokines and chemokines (n=48 total) in the peripheral blood from patients enrolled in the clinical trial is therefore also being assessed.ConclusionsOur correlative analysis of paired biopsies and peripheral blood from a novel clinical trial of XL888 and pembrolizumab will allow for further mechanistic insight into treatment-induced immune modulation. These data will also serve to validate whether alterations of CAF phenotype, cytokine and chemokine release, and T cell infiltration observed preclinically are mirrored in patients.Trial RegistrationThis clinical trial is underway and registered with the ID NCT03095781.Ethics ApprovalThe study was approved by Emory University’s Ethics Board, approval IRB00087397.ReferenceZhang Y, Ware MB, Zaidi M, Ruggieri AN, Olson B, Komar H, Farren MR, Nagaraju GP, Zhang C, Chen Z, Sarmiento J, Ahmed R, Maithel SK, El-Rayes BF, Lesinski GB. Heat shock protein-90 inhibition alters activation of pancreatic stellate cells and enhances the efficacy of PD-1 blockade in pancreatic cancer. Molecular Cancer Therapeutics 2020.

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Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2009-07-235143 ◽

2010 ◽

Vol 115 (9) ◽

pp. 1735-1745 ◽

Cited By ~ 46

Author(s):

Takaomi Sanda ◽

Xiaoyu Li ◽

Alejandro Gutierrez ◽

Yebin Ahn ◽

Donna S. Neuberg ◽

...

Keyword(s):

Gene Expression ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Heat Shock ◽

Heat Shock Protein ◽

Histone Deacetylase ◽

Lymphoblastic Leukemia ◽

Proteasome Inhibitors ◽

Heat Shock Protein 90 ◽

Cell Acute Lymphoblastic Leukemia

Abstract To identify dysregulated pathways in distinct phases of NOTCH1-mediated T-cell leukemogenesis, as well as small-molecule inhibitors that could synergize with or substitute for γ-secretase inhibitors (GSIs) in T-cell acute lymphoblastic leukemia (T-ALL) therapy, we compared gene expression profiles in a Notch1-induced mouse model of T-ALL with those in human T-ALL. The overall patterns of NOTCH1-mediated gene expression in human and mouse T-ALLs were remarkably similar, as defined early in transformation in the mouse by the regulation of MYC and its target genes and activation of nuclear factor-κB and PI3K/AKT pathways. Later events in murine Notch1-mediated leukemogenesis included down-regulation of genes encoding tumor suppressors and negative cell cycle regulators. Gene set enrichment analysis and connectivity map algorithm predicted that small-molecule inhibitors, including heat-shock protein 90, histone deacetylase, PI3K/AKT, and proteasome inhibitors, could reverse the gene expression changes induced by NOTCH1. When tested in vitro, histone deacetylase, PI3K and proteasome inhibitors synergized with GSI in suppressing T-ALL cell growth in GSI-sensitive cells. Interestingly, alvespimycin, a potent inhibitor of the heat-shock protein 90 molecular chaperone, markedly inhibited the growth of both GSI-sensitive and -resistant T-ALL cells, suggesting that its loss disrupts signal transduction pathways crucial for the growth and survival of T-ALL cells.

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Heat Shock Protein-90 Inhibitors Enhance Antigen Expression on Melanomas and Increase T Cell Recognition of Tumor Cells

PLoS ONE ◽

10.1371/journal.pone.0114506 ◽

2014 ◽

Vol 9 (12) ◽

pp. e114506 ◽

Cited By ~ 15

Author(s):

Timothy J. Haggerty ◽

Ian S. Dunn ◽

Lenora B. Rose ◽

Estelle E. Newton ◽

Franco Pandolfi ◽

...

Keyword(s):

T Cell ◽

Heat Shock ◽

Heat Shock Protein ◽

Tumor Cells ◽

Heat Shock Protein 90 ◽

Antigen Expression ◽

Cell Recognition ◽

T Cell Recognition

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Limiting dilution analysis of proliferative T cell responses to mycobacterial 65-kDa heat-shock protein fails to show significant frequency differences between synovial fluid and peripheral blood of patients with rheumatoid arthritis

European Journal of Immunology ◽

10.1002/eji.1830211207 ◽

1991 ◽

Vol 21 (12) ◽

pp. 2937-2941 ◽

Cited By ~ 32

Author(s):

Heinrich Peter Fischer ◽

Claire E. M. Sharrock ◽

M. J. Colston ◽

Gabriel S. Panayi

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

Heat Shock ◽

Synovial Fluid ◽

Heat Shock Protein ◽

Peripheral Blood ◽

T Cell Responses ◽

Significant Frequency ◽

Cell Responses ◽

Limiting Dilution

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Contents of testosterone, testosterone receptor, and heat shock protein 90 in the peripheral blood and testicular tissue of azoospermia patients

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2014.01159 ◽

2014 ◽

Vol 35 (10) ◽

pp. 1159

Author(s):

Ying WANG ◽

Yong-jie LIU ◽

Fang LIU ◽

Gang BAI ◽

Da-wei TANG ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Peripheral Blood ◽

Heat Shock Protein 90 ◽

Testicular Tissue

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Accumulation of Human Heat Shock Protein 60-Reactive T Cells in the Gingival Tissues of Periodontitis Patients

Infection and Immunity ◽

10.1128/iai.70.5.2492-2501.2002 ◽

2002 ◽

Vol 70 (5) ◽

pp. 2492-2501 ◽

Cited By ~ 74

Author(s):

Kazuhisa Yamazaki ◽

Yutaka Ohsawa ◽

Koichi Tabeta ◽

Harue Ito ◽

Kaoru Ueki ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Heat Shock ◽

Heat Shock Protein ◽

Peripheral Blood ◽

Cytokine Profile ◽

T Cell Clones ◽

Cell Clones ◽

Ifn Γ ◽

Human Hsp60

ABSTRACT Heat shock protein 60s (hsp60) are remarkably immunogenic, and both T-cell and antibody responses to hsp60 have been reported in various inflammatory conditions. To clarify the role of hsp60 in T-cell responses in periodontitis, we examined the proliferative response of peripheral blood mononuclear cells (PBMC), as well as the cytokine profile and T-cell clonality, for periodontitis patients and controls following stimulation with recombinant human hsp60 and Porphyromonas gingivalis GroEL. To confirm the infiltration of hsp60-reactive T-cell clones into periodontitis lesions, nucleotide sequences within complementarity-determining region 3 of the T-cell receptor (TCR) β-chain were compared between hsp60-reactive peripheral blood T cells and periodontitis lesion-infiltrating T cells. Periodontitis patients demonstrated significantly higher proliferative responses of PBMC to human hsp60, but not to P. gingivalis GroEL, than control subjects. The response was inhibited by anti-major histocompatibility complex class II antibodies. Analysis of the nucleotide sequences of the TCR demonstrated that human hsp60-reactive T-cell clones and periodontitis lesion-infiltrating T cells have the same receptors, suggesting that hsp60-reactive T cells accumulate in periodontitis lesions. Analysis of the cytokine profile demonstrated that hsp60-reactive PBMC produced significant levels of gamma interferon (IFN-γ) in periodontitis patients, whereas P. gingivalis GroEL did not induce any skewing toward a type1 or type2 cytokine profile. In control subjects no significant expression of IFN-γ or interleukin 4 was induced. These results suggest that periodontitis patients have human hsp60-reactive T cells with a type 1 cytokine profile in their peripheral blood T-cell pools.

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