Phase II Trial of Talabostat and Docetaxel in Advanced Non-small Cell Lung Cancer

Eager, Rob; Cunningham, Charles; Senzer, Neil; Richards, Donald A.; Raju, Robert N.; Jones, Barry; Uprichard, M. J.; Nemunaitis, John

doi:10.1016/j.clon.2009.04.007

Cited by 77 publications

(43 citation statements)

References 27 publications

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“…In subsequent phase II trials in combination with standard cytotoxic chemotherapy, however, Val-boroPro did not meet the endpoints for efficacy [44], [45], . Based on the data presented here, we propose that Val-boroPro and other similar compounds with anti-tumor activity would be far more likely to produce clinical tumor responses when used as immunotherapeutic adjuvants rather than in combination with cytotoxic agents.…”

Section: Discussionmentioning

confidence: 99%

Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors

Walsh

Duncan²,

Larabee³

et al. 2013

PLoS ONE

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Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine.

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Section: Discussionmentioning

confidence: 99%

Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors

Walsh

Duncan²,

Larabee³

et al. 2013

PLoS ONE

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“…Talabostat selectively inhibits both FAP and DPPIV, and it stimulates the production of immunomodulatory cytokines and chemokines through a mechanism that is not completely understood (65, 66). In phase II clinical trials, talabostat has been tested alone or in combination as therapy for metastatic colorectal cancer (49), NSCLC (67), stage IV melanoma (68), and chronic lymphocytic leukemia (66). Although one complete response (in NSCLC) and a few partial responses were reported in these studies, no clinical benefit could be attributed to talabostat or combination therapy over the single-agent, standard-of-care arms in the studies.…”

Section: Potential For Therapeutic Exploitation Of Fap By a Novel Promentioning

confidence: 99%

Rationale Behind Targeting Fibroblast Activation Protein–Expressing Carcinoma-Associated Fibroblasts as a Novel Chemotherapeutic Strategy

Brennen

Isaacs

Denmeade

2012

Molecular Cancer Therapeutics

211

199

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The tumor microenvironment has emerged as a novel chemotherapeutic strategy in the treatment of cancer. This is most clearly exemplified by the antiangiogenesis class of compounds. Therapeutic strategies that target fibroblasts within the tumor stroma offer another treatment option. However, despite promising data obtained in preclinical models, such strategies have not been widely used in the clinical setting, largely due to a lack of effective treatments that specifically target this population of cells. The identification of fibroblast activation protein α (FAP) as a target selectively expressed on fibroblasts within the tumor stroma or on carcinoma-associated fibroblasts led to intensive efforts to exploit this novel cellular target for clinical benefit. FAP is a membrane-bound serine protease of the prolyl oligopeptidase family with unique post-prolyl endopeptidase activity. Until recently, the majority of FAP-based therapeutic approaches focused on the development of small-molecule inhibitors of enzymatic activity. Evidence suggests, however, that FAP’s pathophysiological role in carcinogenesis may be highly contextual, depending on both the exact nature of the tumor microenvironment present and the cancer type in question to determine its tumor-promoting or tumor-suppressing phenotype. As an alternative strategy, we are taking advantage of FAP’s restricted expression and unique substrate preferences to develop a FAP-activated prodrug to target the activation of a cytotoxic compound within the tumor stroma. Of note, this strategy would be effective independently of FAP’s role in tumor progression because its therapeutic benefit would rely on FAP’s localization and activity within the tumor microenvironment rather than strictly on inhibition of its function.

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“…We and others have shown that oral administration of PT-100 mediates complete regression in multiple tumor models 21,22 . In addition, PT-100 achieved partial responses in patients with stage IV melanoma, and both partial and complete responses in non-small cell lung carcinoma 23,24 . Previous studies with PT-100 demonstrated that it appears to stimulate tumor immunity via the upregulation of cytokine and chemokine expression in tumor and lymphoid tissues 21 .…”

Section: Introductionmentioning

confidence: 99%

A Pan-Inhibitor of DASH Family Enzymes Induces Immune-mediated Regression of Murine Sarcoma and Is a Potent Adjuvant to Dendritic Cell Vaccination and Adoptive T-cell Therapy

Duncan¹,

Highfill

Qin

et al. 2013

Journal of Immunotherapy

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Current multimodality therapy consisting of surgery, chemotherapy and radiation will fail in approximately 40% of patients with pediatric sarcomas and results in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (Dipeptidyl peptidase IV activity and/or structural homologues) enzymes can mediate tumor regression via immune-mediated mechanisms. Here we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma (RMS) cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b+) cells, particularly myeloid dendritic cells (DCs), to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11b+Ly6-ChiLy6-Glo) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1-/-) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared to either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies particularly as an adjuvant to tumor vaccines and ACT.

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Phase II Trial of Talabostat and Docetaxel in Advanced Non-small Cell Lung Cancer

Cited by 77 publications

References 27 publications

Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors

Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors

Rationale Behind Targeting Fibroblast Activation Protein–Expressing Carcinoma-Associated Fibroblasts as a Novel Chemotherapeutic Strategy

A Pan-Inhibitor of DASH Family Enzymes Induces Immune-mediated Regression of Murine Sarcoma and Is a Potent Adjuvant to Dendritic Cell Vaccination and Adoptive T-cell Therapy

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