Number of Treatment Cycles Influences Development of Cytotoxic T Cells in Metastatic Breast Cancer Patients – A Phase I/II Study

Abstract

The influence of the number of apheresis-stimulation-infusion(s) cycles, and the time in culture before the infusion (one vs. two weeks), on the generation of tumor antigen-specific cytotoxic T-lymphocytes (CTL) was investigated in a phase I/II clinical adoptive immunotherapy trial. Two previously treated metastatic breast cancer patients with no evidence of disease, in complete remission (CR), were enrolled. Each apheretic peripheral blood mononuclear cell (PBMC) sample was stimulated twice with MUC-1 before infusion back into the patients. Killer T-cells responses against MUC-1-expressing MCF-7 (CTL), nonspecific natural killer (NK) and lymphokine-activated killer (LAK) target cell lines, as well as, cytokine production were measured before each infusion. Patients received 2 infusions per month for 4 months. There were no tumor recurrences or toxicity. CTL, NK and LAK cells, type 1 cytokine, gamma-interferon (G-INF), and CD4(+) and CD8(+) memory T-lymphocytes were initially generated, produced or induced, respectively, and then declined. The CTL, NK and LAK cells were only induced at the first infusion of the first month. Thus, maintaining PBMC in culture longer than the first infusion was of no benefit with regards to retaining functional killer T-cells. In conclusion, this study implies that one treatment is optimal.

Retracted: Antitumor activity of human γδ T cells transducted with CD8 and with T‐cell receptors of tumor‐specific cytotoxic T lymphocytes

“…Although several studies demonstrate that autologous ex vivo-generated antitumor CTL can be administered safely in patients with advanced solid tumors and can improve the immunological antitumor reactivity in recipients, the strategy is hampered by the difficulty of isolating and expanding a sufficient quantity of autologous tumor-reactive T cells capable of preserving the cytotoxic capacity. (15,16) Several investigators have reported TCR transduction technology with retroviral vectors enables generation of novel effectors that demonstrate HLA-restricted, antigen-specific CTL functions. (17,18) The transduction of the TCRab genes facilitates production of a large number of antitumor effectors functionally similar to CTL activity in a reproducible fashion without laborious techniques.…”

Immune System and the Efficacy of Cancer Treatment

“…Показано, что эффективное цитостатическое лечение связано с проявлением цитотоксической активности эффекторов иммунной системы в отношении опухолевых клеток (Mozaffari F. et al, 2007; Предисловие 7 Wright S.E. et al, 2010;Zhang Y. et al, 2007), которая индуцируется de novo или стимулируется под влиянием лучевой или химиотерапии.…”

“…Многими авторами показано, что высокий уровень CD8-T-лимфоцитов, как и его сочетание с уменьшением числа внутриопухолевых CD4+CD25+FOXP3+ Т-регуляторных клеток ассоциировано с улучшением показателей выживаемости пациентов с различными солидными опухолями, получавших терапию (Senovilla L. et al, 2012;Pol J. et al, 2015). Очевидно, что увеличение эффективности цитостатических агентов связано в первую очередь с цитотоксической активностью клеток иммунной системы в отношении опухолевых клеток, которую в этих условиях проявляют как Т-лимфоциты, так и NK-клетки (Mozaffari F. et al, 2007;Wright S.E. et al, 2010;Zhang Y. et al, 2007).…”

Human Dendritic Cells Engineered to Secrete Interleukin-18 Activate MAGE-A3-Specific Cytotoxic T Lymphocytesin vitro

“…Adoptive cell transfer (ACT) immunotherapy, which utilizes autologous antigen-specific CTLs that have been activated and expanded ex vivo (Wright et al, 2010), has been studied extensively as a potential cancer therapy (Dudley et al, 2005;Rosenberg, 2004) and has been shown to be promising for the treatment of some virus-associated malignancies, such as Epstein-Barr virus-positive posttransplant lymphoproliferative disease (Rooney et al, 1997), as well as for the treatment of advanced melanoma (Morgan et al, 2006).…”