A phase I study of adoptive immunotherapy for recurrent non-small-cell lung cancer patients with autologous γδ T cells☆☆☆

Nakajima, Jun; Murakawa, Tomohiro; Fukami, Takeshi; Goto, Shigenori; Kaneko, Toru; Yoshida, Yukihiro; Takamoto, Shinichi; Kakimi, Kazuhiro

doi:10.1016/j.ejcts.2009.11.051

Cited by 158 publications

(126 citation statements)

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“…Furthermore, six patients were alive at the end of the observation (240-850 days), demonstrating the potential of cd cell therapy for this condition. 45 Likewise, Nicol's team in Brisbane, Australia recently reported that when autologous transplants of In 111 -radiolabelled TCRVc9Vd2 1 cd T cells were tracked in 18 patients with advanced stages of various solid tumors, the cells trafficked predominantly to the lungs, liver and spleen in all patients but also to metastatic tumor sites in some patients. No dose-limiting toxicity was reported in this study, and three out of the 18 patients had clinical responses while continuing their previously ineffective chemotherapy.…”

Section: Rationale For Harnessing CD Cells In Cancer Immunotherapymentioning

confidence: 99%

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

et al. 2012

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During the last several years, research has produced a significant amount of knowledge concerning the characteristics of human cd T lymphocytes. Findings regarding the immune functions of these cells, particularly their natural killer cell-like lytic activity against tumor cells, have raised expectations for the therapeutic applications of these cells for cancer. Pharmaceutical companies have produced selective agonists for these lymphocytes, and several teams have launched clinical trials of cd T cell-based cancer therapies. The findings from these studies include hematological malignancies (follicular lymphoma, multiple myeloma, acute and chronic myeloid leukemia), as well as solid tumors (renal cell, breast and prostate carcinomas), consisting of samples from more than 250 patients from Europe, Japan and the United States. The results of these pioneering studies are now available, and this short review summarizes the lessons learned and the role of cd T cell-based strategies in the current landscape of cancer immunotherapies.

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Section: Rationale For Harnessing CD Cells In Cancer Immunotherapymentioning

confidence: 99%

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

et al. 2012

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“…PBMCs were used as the normal control target. Three thousand target cells labeled with 51 Cr sodium chromate (0.2 mCi/10 6 cells; Amersham Saclay, France) were cocultured in complete medium (RPMI) in 96-well U-bottomed plates for 4 hr with Vc9Vd2 T cells. The effector to target ratio (E:T) ranged from 1:1 to 60:1.…”

Section: Cytotoxicity Assays and Blocking Monoclonal Antibodiesmentioning

confidence: 99%

“…The expanded Vc9Vd2 T cells were tested for cytotoxicity against the EOC cell lines and autologous tumor cells from the primary tumor, carcinomatosis and ascites in a 4-hr standard 51 Cr release assay. PBMCs were used as the normal control target.…”

Section: Cytotoxicity Assays and Blocking Monoclonal Antibodiesmentioning

confidence: 99%

“…The effector to target ratio (E:T) ranged from 1:1 to 60:1. The 51 Cr release was assessed in the culture supernatants, using a Top-count gamma counter (Packard Instrument, Gromingen, The Netherlands). The specific lysis (expressed as a percentage) was calculated using the standard formula: [(mean experimental cpm À mean spontaneous cpm)/(mean maximum cpm À mean spontaneous cpm)] Â 100.…”

Section: Cytotoxicity Assays and Blocking Monoclonal Antibodiesmentioning

confidence: 99%

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Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vγ9Vδ2 T cells impaired by the prostaglandin E2 immunosuppressive factor: Implications for immunotherapy

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Toutirais

et al. 2011

Intl Journal of Cancer

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Epithelial ovarian cancer (EOC) usually spreads into the peritoneal cavity, thereby providing an opportunity for intraperitoneal adoptive immunotherapy with Vc9Vd2 T lymphocytes, a T cell subpopulation endowed with high lytic properties against tumor cells. However, previous studies have reported that Vc9Vd2 T cells fail to expand from peripheral blood mononuclear cells in one-third of patients with cancer. Here, from a cohort of 37 patients with EOC, a multiple correspondence analysis identified three populations, one of which was not suitable for Vc9Vd2 T-cell adoptive therapy. Interestingly, the ineligible patients were identified based on the frequency of Vc9Vd2 T cells in their peripheral blood and the patients' age. The average time to tumor recurrence was also found to be significantly different between the three populations, suggesting that the innate immune response is involved in EOC prognosis. A dramatic decrease in the lytic properties of Vc9Vd2 T cells occurred following incubation with ascitic supernatant and was found to be associated with reduced perforin/granzyme degranulation. Prostaglandin E2, but not IL-6, IL-10, VEGF or TGF-b, showed immunosuppressive effects in Vc9Vd2 T cells. Interestingly, our results emphasize that pretreating ovarian tumor cells with zoledronate partially reverses the immunosuppressive effects of ovarian cancer-associated ascites and restores a high level of lytic activity. These data sustain that optimal Vc9Vd2 T-cell adoptive immunotherapy previously requires counteracting the tumor immunosuppressive microenvironment. Altogether, our findings provide a rationale for clinically evaluating Vc9Vd2 T-cell adoptive immunotherapy with intraperitoneal carcinomatosis presensitization by zoledronate in patients with EOC.Epithelial ovarian cancer (EOC) is the fifth most frequent cancer among women and the fourth most common cause of cancer-related deaths among women.1 More than 70% of patients are diagnosed when the cancer has spread beyond the ovaries, and these patients have low median survival rates.2 The prognosis is poor, with a 5-year survival rate of only 30%, and the rate is less than 10% for patients with bulky residual disease remaining after surgery and chemotherapy, which emphasizes the need for innovative treatments.3 The inflammatory microenvironment of ovarian carcinomas prevents the maturation of myeloid cells, favors regulatory T-cell development and restrains the cytotoxic activity of effector T lymphocytes, leading to the escape of the tumor from the immune system. 4 Thus, research is ongoing to develop innovative approaches aimed at stimulating the immune system. 5 The preferential spread pattern of EOC in the peritoneal cavity offers an excellent opportunity for the regional administration of adoptive T-cell therapy.2 Some pilot trials have shown the feasibility of and promising

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“…138 For adoptive transfer therapy, a single dose as large as 10 9 ex vivo expanded Vc9Vd2 cd-T cells has been confirmed to be safe by several independent investigations. [139][140][141] Encouragingly, these infused Vc9Vd2 cd-T cells exhibited satisfactory clinical benefit in an anti-tumor trial. 142 For in vivo applications, a single dose of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate plus 5 days of IL-2 treatment induced an 80-fold expansion of macaque peripheral blood Vc9Vd2 cd-T cells without detectable side effects.…”

Section: Current Strategies For Activating or Expanding Cd-t Cellsmentioning

confidence: 96%

γδ-T cells: an unpolished sword in human anti-infection immunity

et al. 2012

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cd-T cells represent a small population of immune cells, but play an indispensable role in host defenses against exogenous pathogens, immune surveillance of endogenous pathogenesis and even homeostasis of the immune system. Activation and expansion of cd-T cells are generally observed in diverse human infectious diseases and correlate with their progression and prognosis. cd-T cells have both 'innate' and 'adaptive' characteristics in the immune response, and their anti-infection activities are mediated by multiple pathways that are under elaborate regulation by other immune components. In this review, we summarize the current state of the literature and the recent advancements in cd-T cell-mediated immune responses against common human infectious pathogens. Although further investigation is needed to improve our understanding of the characteristics of different cd-T cell subpopulations under specific conditions, cd-T cell-based therapy has great potential for the treatment of infectious diseases.

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A phase I study of adoptive immunotherapy for recurrent non-small-cell lung cancer patients with autologous γδ T cells☆☆☆

Abstract: We suggest that gammadelta T-cell immunotherapy might be safe and feasible for patients with recurrent non-small-cell lung cancer.

Cited by 158 publications

References 16 publications

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vγ9Vδ2 T cells impaired by the prostaglandin E2 immunosuppressive factor: Implications for immunotherapy

γδ-T cells: an unpolished sword in human anti-infection immunity

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