In vivo manipulation of Vγ9Vδ2 T cells with zoledronate and low‐dose interleukin‐2 for immunotherapy of advanced breast cancer patients

The potent anti‐tumour activities of γδ T cells have prompted the development of protocols in which γδ‐agonists are administered to cancer patients. Encouraging results from small Phase I trials have fuelled efforts to characterize more clearly the application of this approach to unmet clinical needs such as metastatic carcinoma. To examine this approach in breast cancer, a Phase I trial was conducted in which zoledronate, a Vγ9Vδ2 T cell agonist, plus low‐dose interleukin (IL)‐2 were administered to 10 therapeutically terminal, advanced metastatic breast cancer patients. Treatment was well tolerated and promoted the effector maturation of Vγ9Vδ2 T cells in all patients. However, a statistically significant correlation of clinical outcome with peripheral Vγ9Vδ2 T cell numbers emerged, as seven patients who failed to sustain Vγ9Vδ2 T cells showed progressive clinical deterioration, while three patients who sustained robust peripheral Vγ9Vδ2 cell populations showed declining CA15‐3 levels and displayed one instance of partial remission and two of stable disease, respectively. In the context of an earlier trial in prostate cancer, these data emphasize the strong linkage of Vγ9Vδ2 T cell status to reduced carcinoma progression, and suggest that zoledronate plus low‐dose IL‐2 offers a novel, safe and feasible approach to enhance this in a subset of treatment‐refractory patients with advanced breast cancer.

[1]  V. Vogel,et al.  Breast cancer risk management. , 2007, Clinical breast cancer.

[2]  R. Mariuzza,et al.  Antigen recognition by human γδ T cells: pattern recognition by the adaptive immune system , 2009, Springer Seminars in Immunopathology.

[3]  J. Wiesner,et al.  Microbial isoprenoid biosynthesis and human γδ T cell activation , 2003, FEBS letters.

[4]  Bruce R. Blazar,et al.  Engineering lymphocyte subsets: tools, trials and tribulations , 2009, Nature Reviews Immunology.

[5]  R. Pazdur,et al.  Approval summary for zoledronic acid for treatment of multiple myeloma and cancer bone metastases. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[7]  FDA approves ZOMETA for treatment of cancer-related bone complications. , 2002, Expert review of anticancer therapy.

[8]  P. Reimer,et al.  Gammadelta T cells for immune therapy of patients with lymphoid malignancies. , 2003, Blood.

[9]  C. Montesano,et al.  Induction of γδ T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo , 2003 .

[10]  T. Fleming,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.

[11]  P. Major.  The use of zoledronic acid, a novel, highly potent bisphosphonate, for the treatment of hypercalcemia of malignancy. , 2002, The oncologist.

[12]  M. Eberl,et al.  Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. , 2007, Cancer research.

[13]  M. Bonneville,et al.  Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. , 1994, Science.

[14]  Gavin P Dunn,et al.  Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. , 2006, Advances in immunology.

[15]  S. Mattarollo,et al.  Chemotherapy pretreatment sensitizes solid tumor‐derived cell lines to Vα24+ NKT cell‐mediated cytotoxicity , 2006, International journal of cancer.

[16]  C. Langford,et al.  Distinct Cytokine-Driven Responses of Activated Blood γδ T Cells: Insights into Unconventional T Cell Pleiotropy1 , 2007, The Journal of Immunology.

[17]  D. Kabelitz,et al.  Perspectives of gammadelta T cells in tumor immunology. , 2007, Cancer research.

[18]  E. Novellino,et al.  Design, synthesis, and biological evaluation of novel aminobisphosphonates possessing an in vivo antitumor activity through a gammadelta-T lymphocytes-mediated activation mechanism. , 2008, Journal of medicinal chemistry.

[19]  E. McFadden,et al.  Toxicity and response criteria of the Eastern Cooperative Oncology Group , 1982, American journal of clinical oncology.

[20]  Wancai Yang,et al.  γδ T Cells Provide an Early Source of Interferon γ in Tumor Immunity , 2003, The Journal of experimental medicine.

[21]  M Van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. , 2000, Journal of the National Cancer Institute.

[22]  Marc Bonneville,et al.  Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. , 2005, Immunity.

[23]  G. De Libero,et al.  Human T Cell Receptor γδ Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells , 2003, The Journal of experimental medicine.

[24]  Yoshimasa Tanaka,et al.  Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma: a pilot study , 2007, Cancer Immunology, Immunotherapy.

[25]  Z. Trajanoski,et al.  Effector memory T cells, early metastasis, and survival in colorectal cancer. , 2005, The New England journal of medicine.

[26]  M. Tiemann,et al.  Sequential application of chemotherapy and monoclonal CD 20 antibody: Successful treatment of advanced composite-lymphoma , 2005, Leukemia & lymphoma.

[27]  T. Spies,et al.  MICA Engagement by Human Vγ2Vδ2 T Cells Enhances Their Antigen-Dependent Effector Function , 2001 .

[28]  M. Gobbi,et al.  Expansion of Vdelta1 T lymphocytes producing IL-4 in low-grade non-Hodgkin lymphomas expressing UL-16-binding proteins. , 2007, Blood.

[29]  A. Hayday.  Gammadelta T cells and the lymphoid stress-surveillance response. , 2009, Immunity.

[30]  B. Melichar,et al.  Tumor-Infiltrating Lymphocytes Predict Response to Neoadjuvant Chemotherapy in Patients with Breast Carcinoma , 2008, Cancer investigation.

[31]  C. Bollard,et al.  Activated Human γδ T Cells as Stimulators of Specific CD8+ T-cell Responses to Subdominant Epstein Barr Virus Epitopes: Potential for Immunotherapy of Cancer , 2009, Journal of immunotherapy.

[32]  P. Tan,et al.  Interaction of current cancer treatments and the immune system: implications for breast cancer therapeutics. , 2008, Expert opinion on pharmacotherapy.

[33]  Kenshi Suzuki,et al.  Clinical and immunological evaluation of zoledronate-activated Vgamma9gammadelta T-cell-based immunotherapy for patients with multiple myeloma. , 2009, Experimental hematology.

[34]  E. Small,et al.  Hormone-Refractory prostate cancer , 2002, Current treatment options in oncology.

[35]  R. Cook,et al.  Efficacy of Bisphosphonates in the Management of Skeletal Complications of Bone Metastases and Selection of Clinical Endpoints , 2002, American journal of clinical oncology.

[36]  F. Poccia,et al.  Differentiation of Effector/Memory Vδ2 T Cells and Migratory Routes in Lymph Nodes or Inflammatory Sites , 2003, The Journal of experimental medicine.

[37]  R. Tampé,et al.  Cross-presenting human γδ T cells induce robust CD8+ αβ T cell responses , 2009, Proceedings of the National Academy of Sciences.

[38]  M. Rimbert,et al.  Phase-I study of Innacell γδ™, an autologous cell-therapy product highly enriched in γ9δ2 T lymphocytes, in combination with IL-2, in patients with metastatic renal cell carcinoma , 2008, Cancer Immunology, Immunotherapy.

[39]  B. Bloom,et al.  Natural and synthetic non-peptide antigens recognized by human γδ T cells , 1995, Nature.

[40]  J. Mönkkönen,et al.  Peripheral blood monocytes are responsible for γδ T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP , 2009, British journal of haematology.

[41]  Wolzt,et al.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. , 2003, The Journal of the American College of Dentists.

[42]  C. Agrati,et al.  In vivo effects of zoledronic acid on peripheral γδ T lymphocytes in early breast cancer patients , 2008, Cancer Immunology and Immunotherapy.

[43]  J. Pelkonen,et al.  The level of ATP analog and isopentenyl pyrophosphate correlates with zoledronic acid-induced apoptosis in cancer cells in vitro. , 2009, Bone.

[44]  S. Rosenberg,et al.  Adoptive immunotherapy for cancer: building on success , 2006, Nature Reviews Immunology.

[45]  B. Robinson,et al.  Immunotherapy and chemotherapy — a practical partnership , 2005, Nature Reviews Cancer.

[46]  Helen Y Wang,et al.  Tumor-Infiltrating γδ T Cells Suppress T and Dendritic Cell Function via Mechanisms Controlled by a Unique Toll-like Receptor Signaling Pathway , 2007 .

[47]  P. Dong,et al.  Endocrine therapy plus zoledronic acid in premenopausal breast cancer. , 2009, The New England journal of medicine.

[48]  D. Scheinberg,et al.  Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  Ennis,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.