A Novel Mouse Model for the Study of Anti-Tumor T Cell Responses in Kras Driven Lung Adenocarcinoma

3091 Background: Our GM.CD40L vaccine (an allogeneic tumor cell-based vaccine generated from human bystander cell line) recruits and activates dendritic cells, which then migrate to regional lymph nodes, where T cell activation occurs, leading to systemic tumor cell killing. The CCL21 chemokine helps to recruit T cells and leads to enhanced T cell responses. The GM.CD40L.CCL21 combination has demonstrated additive effects in NSCLC mouse models. Methods: We initiated a phase I/II randomized study to evaluate GM.CD40L (Arm A) vs. GM.CD40L.CCL21 (Arm B) in patients with lung adenocarcinoma who had failed first-line therapy. Primary endpoints were safety and tolerability of Arm B in phase I and progression-free survival (PFS) in phase II; secondary endpoints included anti-tumor immune responses/T-cell responses by ELISpot assay on PBMC. Immune-related response criteria as determined by the investigator served to determine discontinuation from study treatment. Intradermal vaccines were administered every 14 days for 3 doses and then monthly X3. A two-stage minimax design was used. Results: In phase I, 3 patients received GM.CD40L.CCL21; no dose-limiting toxicities occurred. Between 4/2012 and 12/2012, Arm A enrolled 11 and Arm B enrolled 16 patients, including those in phase I (median age: 70/67.5 years, females: 45.5%/37.5%, PS1: 54.5%/75%, median prior regimens: 3/5 for Arm A vs. Arm B, respectively). Most common toxicities for Arm A vs. Arm B were injection site reaction (45.5%/43.8%), fatigue (9.1%/37.5%), anorexia (0%/12.5%), and pain in extremity (0%/12.5%). Median PFS for Arm A vs. B was 4.4 vs. 4.4 months (p=0.37). Of the 6 patients who remained on study post RECIST v1.1 progression, all demonstrated further progression on subsequent scans and were removed from the study. Of patients evaluable for efficacy, stable disease was 3/7 and progressive disease was 6/7 for Arm A vs. Arm B, respectively. Analyses of ELISpot assay on the PBMC are underway. Conclusions: GM.CD40L.CCL21 vaccine is well tolerated; thus far, median PFS results are similar to GM.CD40L vaccine. Updated results of the phase II trial will be presented. Clinical trial information: NCT01433172.

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Gemcitabine induces phenotypic alterations of tumor cells that facilitate antitumor T cell responses in a mouse model of oral cancer

International Journal of Oral and Maxillofacial Surgery ◽

10.1016/j.ijom.2013.07.372 ◽

2013 ◽

Vol 42 (10) ◽

pp. 1282-1283

Author(s):

K. Tomihara ◽

N. Arai ◽

M. Noguchi

Keyword(s):

T Cell ◽

Oral Cancer ◽

Mouse Model ◽

Tumor Cells ◽

T Cell Responses ◽

Cell Responses

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Development of an orthotopic HCC mouse model for analysis of tumor-specific CD8 T cell responses

Zeitschrift für Gastroenterologie ◽

10.1055/s-0032-1332087 ◽

2013 ◽

Vol 51 (01) ◽

Author(s):

D Ostroumov

Keyword(s):

T Cell ◽

Mouse Model ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses

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Crimean-Congo Hemorrhagic Fever Mouse Model Recapitulating Human Convalescence

Journal of Virology ◽

10.1128/jvi.00554-19 ◽

2019 ◽

Vol 93 (18) ◽

Cited By ~ 4

Author(s):

David W. Hawman ◽

Kimberly Meade-White ◽

Elaine Haddock ◽

Rumi Habib ◽

Dana Scott ◽

...

Keyword(s):

T Cell ◽

Mouse Model ◽

Immune Responses ◽

Severe Disease ◽

Small Animal ◽

T Cell Responses ◽

Hemorrhagic Fever ◽

Type I ◽

Crimean Congo Hemorrhagic Fever ◽

Cell Responses

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is a cause of severe hemorrhagic fever. Its tick reservoir and vector are widely distributed throughout Africa, Southern and Eastern Europe, the Middle East, and Asia. Serological evidence suggests that CCHFV can productively infect a wide variety of species, but only humans develop severe, sometimes fatal disease. The role of the host adaptive immunity in control or contribution to the severe pathology seen in CCHF cases is largely unknown. Studies of adaptive immune responses to CCHFV have been limited due to lack of suitable small animal models. Wild-type mice are resistant to CCHFV infection, and type I interferon-deficient mice typically develop a rapid-onset fatal disease prior to development of adaptive immune responses. We report here a mouse model in which type I interferon-deficient mice infected with a clinical isolate of CCHFV develop a severe inflammatory disease but ultimately recover. Recovery was coincident with development of CCHFV-specific B- and T-cell responses that were sustained for weeks postinfection. We also found that recovery from a primary CCHFV infection could protect against disease following homologous or heterologous reinfection. Together this model enables study of multiple aspects of CCHFV pathogenesis, including convalescence, an important aspect of CCHF disease that existing mouse models have been unsuitable for studying. IMPORTANCE The role of antibody or virus-specific T-cell responses in control of acute Crimean-Congo hemorrhagic fever virus infection is largely unclear. This is a critical gap in our understanding of CCHF, and investigation of convalescence following severe acute CCHF has been limited by the lack of suitable small animal models. We report here a mouse model of CCHF in which infected mice develop severe disease but ultimately recover. Although mice developed an inflammatory immune response along with severe liver and spleen pathology, these mice also developed CCHFV-specific B- and T-cell responses and were protected from reinfection. This model provides a valuable tool to investigate how host immune responses control acute CCHFV infection and how these responses may contribute to the severe disease seen in CCHFV-infected humans in order to develop therapeutic interventions that promote protective immune responses.

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