Activated T-Cell and Bispecific Antibody Immunotherapy for High-Risk Breast Cancer

Lum, Lawrence G.; Sen, Manjula

doi:10.1159/000046554

Cited by 18 publications

(11 citation statements)

References 10 publications

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“…Furthermore, we may need to escalate the dose of BSAbxCA125 to overcome the nonspecific binding. Lum et al showed that it is feasible to treat patients with up to 2 Â 10 9 bispecific antibody-treated effector T cells/kg without significant toxicity (38). Thus, it may be safe and efficacious to administer large quantities of bispecific antibody in an effort to improve the efficacy of CIK cells.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Killing of Primary Ovarian Cancer by Retargeting Autologous Cytokine-Induced Killer Cells with Bispecific Antibodies: A Preclinical Study

Chan¹,

Hamilton²,

Cheung³

et al. 2006

Clinical Cancer Research

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112

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Cr release assay of fresh ovarian cancer cells exposed to autologous CIK cells increased from 21.7 F 0.3% to 89.4 F 2.1% at an E:Tratio of100:1 (P < 0.001). Anti-NKG2D antibodies attenuated the CIK activity by 56.8% on primary cells (P < 0.001). In a xenograft severe combined immunodeficient mouse model, real-time tumor regression and progression was visualized using a noninvasive in vivo bioluminescence imaging system. Four hours after CIK cell injection, we were able to visualize CD8 + NKG2D + CIK cells infiltrating Her2-expressing cancer cells on fluorescence microscopy. Mice that underwent adoptive transfer of CIK cells redirected with BSAbxCA125 and BSAbxHer2 had significant reduction in tumor burden (P < 0.001and P < 0.001) and improvement in survival (P = 0.05 and P = 0.006) versus those treated with CIK cells alone. Bispecific antibodies significantly enhanced the cytotoxicity of CIK cells in primary ovarian cancer cells and in our in vivo mouse model. The mechanism of cytolysis seems to be mediated in part by the NKG2D receptor.

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Section: Discussionmentioning

confidence: 99%

Enhanced Killing of Primary Ovarian Cancer by Retargeting Autologous Cytokine-Induced Killer Cells with Bispecific Antibodies: A Preclinical Study

Chan¹,

Hamilton²,

Cheung³

et al. 2006

Clinical Cancer Research

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112

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“…Early clinical studies in metastatic breast cancer show some efficacy of this strategy. 36,37 Others have explored using HDC followed by autologous transplantation to first cyto-reduce disease, and then employing allogenic transplantation to optimize GVT effect. 38,39 The concept of inhibiting tumor angiogenesis as a method of cancer treatment and/or prevention was originally proposed over 30 years ago; however, it is not until recently that we have had the development of effective in vivo antiangiogenic strategies allowing for translational medicine.…”

Section: Discussionmentioning

confidence: 99%

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-γ after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer

Vahdat

Cohen

Zipin

et al. 2007

Bone Marrow Transplant

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High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m 2 SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to þ 28 and interferon gamma (IFN-c) 0.025 mg/m 2 SQ every 2 days from day þ 7 to þ 28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-c arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.

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“…A Phase III randomized trial is being pursued as a result of this work. Compared with an historic control group, Lum and Sen also observed improved cytokine production, T‐cell activity, and survival in a similar patient group after treatment with IL‐2, GM‐CSF, and activated T‐cells armed with anti‐CD3 × anti‐HER2/ neu bispecific antibody 85…”

Section: Antitumor Activity Of Gm‐csf Therapy Alonementioning

confidence: 92%

“…Compared with an historic control group, Lum and Sen also observed improved cytokine production, T-cell activity, and survival in a similar patient group after treatment with IL-2, GM-CSF, and activated T-cells armed with anti-CD3 ϫ anti-HER2/ neu bispecific antibody. 85 Prostate carcinoma. Evaluation of GM-CSF for the treatment of patients with prostate carcinoma has been assessed by changes in PSA levels.…”

Section: Nonhematologic Malignanciesmentioning

confidence: 99%

Modulation of antitumor immune responses by hematopoietic cytokines

Waller¹,

Ernstoff²

2003

Cancer

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BACKGROUNDAdvances in immunotherapy for the treatment of patients with malignant disease have led to increasingly successful use of these methods in the clinical setting. This review presents findings from recent studies that have explored improved methods for the presentation of tumor‐associated antigens and for the restoration of tumor specific immune responses using cytokine therapy.METHODSA review of human clinical trial research on immune cytokines from 1995 (MEDLINE) to the present was conducted. Particular attention was focused on articles that reported results from Phase II or later clinical studies in patients with malignant disease.RESULTSThe defects in cellular immunity commonly seen in patients with malignancies often are expressed as tumor specific anergy. Reversing patient tolerance to tumor antigens may be accomplished by treatment with immunoregulatory cytokines, such as Flt‐3 and granulocyte‐macrophage–colony stimulating factor, that mature and activate dendritic cells. Published clinical studies indicate that granulocyte‐macrophage–colony stimulating factor stimulates antigen‐presenting cells and has promising antitumor activity as an adjunct or as stand‐alone therapy for patients with malignant disease, including leukemia, melanoma, breast carcinoma, prostate carcinoma, and renal cell carcinoma.CONCLUSIONSImmune‐modulating cytokines may be used alone or in combination with other treatments to help restore immune function, improve response to tumor‐associated antigens, and reduce the toxic effects of standard antitumor therapies. The evolving understanding of how dendritic cells regulate immune responses and promising results from published studies of immune‐enhancing cytokines in the treatment of patients with malignant disease support the conduct of randomized clinical trials to confirm the clinical benefit of these immunotherapeutic strategies. Cancer 2003;97:1797–809. © 2003 American Cancer Society.DOI 10.1002/cncr.11247

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Activated T-Cell and Bispecific Antibody Immunotherapy for High-Risk Breast Cancer

Cited by 18 publications

References 10 publications

Enhanced Killing of Primary Ovarian Cancer by Retargeting Autologous Cytokine-Induced Killer Cells with Bispecific Antibodies: A Preclinical Study

Enhanced Killing of Primary Ovarian Cancer by Retargeting Autologous Cytokine-Induced Killer Cells with Bispecific Antibodies: A Preclinical Study

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-γ after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer

Modulation of antitumor immune responses by hematopoietic cytokines

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