BAT monoclonal antibody immunotherapy of human metastatic colorectal carcinoma in mice

Stromal fibroblasts are important for normal breast homeostasis and regulation of epithelial growth; however, this regulatory function is altered during carcinogenesis. To study the role of fibroblasts in the development of breast cancer, fibroblasts derived from normal breast (NAFs) were incorporated into the MCF10AT xenograft model of progressive proliferative breast disease. The persistence of human NAFs in xenografts was established by intracellular labeling and tyramide-coupled fluorescent in situ hybridization. Overall, the number of MCF10AT epithelial structures was decreased, and the rate of epithelial cell apoptosis was increased in xenografts containing NAFs. However, these changes were primarily in low-grade epithelial structures, corresponding to normal or mildly hyperplastic ductal epithelium. The level and rate of apoptosis of high-grade epithelial structures, corresponding to in situ and invasive carcinoma, were not consistently altered by NAFs. In addition, there was variability in the growth-inhibitory capacity of NAFs derived from different individuals. NAFs induced changes in the morphology of high-grade MCF10AT structures and in xenograft stroma, including the composition of extracellular matrix, and increased angiogenesis and lymphocytic infiltration. These findings imply that NAFs can inhibit the growth of normal and hyperplastic epithelium but are less able to regulate the more transformed epithelial cells that arise during carcinogenesis. (Am J Pathol 2007, 170

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“…28,29 As expected, infiltration by CD3-positive lymphocytes was overall lower than B220-positive, B-cell infiltration.…”

Section: Inflammatory Infiltratesupporting

confidence: 73%

“…27 CD3-, CD4-, and CD8-positive T cells have been identified in low numbers in athymic mice, 28 and there are reports of extra-thymic maturation of T cells. 28,29 As expected, infiltration by CD3-positive lymphocytes was overall lower than B220-positive, B-cell infiltration.…”

Section: Inflammatory Infiltratementioning

confidence: 99%

Human Breast Fibroblasts Inhibit Growth of the MCF10AT Xenograft Model of Proliferative Breast Disease

Sadlonova

Mukherjee

Bowe

et al. 2007

The American Journal of Pathology

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“…In nude mice, Ab treatment was previously demonstrated to reduce liver metastasis outgrowth as well (37,38). However, this may not represent the most optimal model to further unravel the mechanisms of Ab therapy as these mice lack T cells, which is compensated by an increased number of NK cells.…”

Section: Discussionmentioning

confidence: 99%

Experimental Antibody Therapy of Liver Metastases Reveals Functional Redundancy between FcγRI and FcγRIV

Otten

Bij

Verbeek

et al. 2008

The Journal of Immunology

108

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Many patients with colorectal cancer will develop liver metastases, even after successful surgical removal of the primary tumor at a time at which no visible metastases are present. We previously demonstrated that surgery--although mandatory--paradoxically enhances the risk of developing liver metastases. Because Ab therapy has been acknowledged as a successful strategy to treat malignancies, we studied the potential of postoperative adjuvant Ab therapy to prevent outgrowth of liver metastases. Treatment with murine anti-gp75 (TA99) mAb completely prevented outgrowth of B16F10 liver metastases in over 90% of mice. Therapeutic efficacy was maintained in either C1q- or complement receptor 3-deficient mice but was completely abrogated in FcR gamma-chain knockout mice. This indicates that the classical complement pathway was not essential, but interaction with activatory Fc gammaR was necessary for successful therapy. TA99-treatment was still effective in Fc gammaRI(-/-), Fc gammaRIII(-/-), Fc gammaRI/III(-/-), and Fc gammaRI/II/III(-/-) mice, suggesting an important role for Fc gammaRIV. However, wild-type mice that were treated with TA99 Abs and an Fc gammaRIV blocking Ab (mAb 9E9) were protected against development of liver metastases as well. Only when both Fc gammaRI and Fc gammaRIV functions were simultaneously inhibited, TA99-mediated curative Ab treatment was abrogated, indicating functional redundancy between both IgG receptors in the liver. Furthermore, depletion of liver macrophages (Kupffer cells) reduced the efficacy of Ab therapy, supporting that Kupffer cells are involved as effector cells. Importantly, since Ab treatment almost completely prevented development of liver metastases, postoperative adjuvant Ab therapy may help to improve patient prognosis.

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“…In preclinical studies, CT-011 and BAT, the mouse monoclonal antibody from which CT-011 was derived, inhibited growth of melanoma, lymphoma, lung, colon, and breast tumors and extended the survival of mice. 14–17 Selective depletion of T or NK cells in tumor-bearing mice reduced the efficacy of BAT, suggesting that both T cells and NK cells are necessary for the in vivo antitumor effect of this antibody. 15 In a phase I clinical trial in patients with advanced hematological malignancies, CT-011 was found to be safe and well tolerated with no observed treatment- or infusion-related serious adverse events.…”

Section: Introductionmentioning

confidence: 99%

Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial

Westin

Chu

Zhang

et al. 2014

The Lancet Oncology

498

310

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Background Endogenous or iatrogenic antitumor immune responses can improve the course of follicular lymphoma (FL), but may be diminished by immune checkpoints in the tumor microenvironment. These may include effects of programmed death (PD)-1, a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. In a Phase II trial, we determined the activity of pidilizumab, a humanized anti-PD-1 monoclonal antibody, with rituximab in patients with relapsed FL. Methods FL patients with rituximab-sensitive disease relapsing after 1–4 prior therapies were eligible. Pidilizumab was administered at 3 mg/kg every 4 weeks for 4 infusions, plus 8 optional infusions every 4 weeks for patients with stable disease or better. Starting 2 weeks after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 weekly for 4 weeks. The primary endpoint was to assess the overall response rate. Analysis was by intention to treat. Peripheral blood and tumor biopsies were studied to assess immunological effects of pidilizumab. This trial has been completed and was registered at www.clinicaltrials.gov as NCT00904722. Findings The combination was well-tolerated, with no autoimmune or therapy-related grade 3/4 toxicities. The most common grade 1 adverse events were anemia (14 patients) and fatigue (13 patients), and the most common grade 2 adverse event was respiratory infection (5 patients). Overall 19/29 (66%) and complete 15/29 (52%) response rates in 29 evaluable patients were high, with tumor regression in 25/29 (86%) of patients. Median progression-free survival was 18.8 months (95% CI: 14.7 months to not reached). The median response duration for the 19 responders was 20.2 months (95% CI: 13.9 months to not reached). Correlative studies of blood and tumor provided insights into predicting response and understanding mechanisms involved. Interpretation Pidilizumab with rituximab is well-tolerated and its activity compared favorably to historical retreatment with rituximab monotherapy in patients with relapsed FL. Our results establish that immune checkpoint blockade is worthy of further study in FL. Funding National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech Ltd, and UT MD Anderson Cancer Center.

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BAT monoclonal antibody immunotherapy of human metastatic colorectal carcinoma in mice

Cited by 11 publications

References 15 publications

Human Breast Fibroblasts Inhibit Growth of the MCF10AT Xenograft Model of Proliferative Breast Disease

Human Breast Fibroblasts Inhibit Growth of the MCF10AT Xenograft Model of Proliferative Breast Disease

Experimental Antibody Therapy of Liver Metastases Reveals Functional Redundancy between FcγRI and FcγRIV

Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial

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