Cancer Immunol Immunother. 2013 May;62(5):909-18. doi: 10.1007/s00262-013-1396-8. Epub 2013 Apr 16.
Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer.
1H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Myeloid-derived suppressor cells (MDSC) are one of the major factors limiting the efficacy of immune therapy. In a clinical trial of patients with extensive stage small cell lung cancer (SCLC), we tested the possibility that targeting MDSC can improve the induction of immune responses by acancer vaccine. Forty-one patients with extensive stage SCLC were randomized into three arms: arm A–control, arm B–vaccination with dendritic cells transduced with wild-type p53, and arm C–vaccination in combination with MDSC targeted therapy with all-trans-retinoic acid (ATRA). Interim results of the ongoing clinical trial are presented. Pre-treatment levels of MDSC populations in patients from all three arms were similar. Vaccine alone did not affect the proportion of MDSC, whereas in patients treated with ATRA, the MDSC decreased more than twofold (p = 0.02). Before the start of treatment, no patients had detectable p53-specific responses in IFN-γ ELISPOT. Sequential measurements did not show positive p53 responses in any of the 14 patients from arm A. After immunization, only 3 out of 15 patients (20 %) from arm B developed a p53-specific response (p = 0.22). In contrast, in arm C, 5 out of 12 patients (41.7 %) had detectable p53 responses (p = 0.012). The proportion of granzyme B-positive CD8(+) T cells was increased only in patients from arm C but not in arm B. Depletion of MDSC substantially improved the immune response to vaccination, suggesting that this approach can be used to enhance the effect of immune interventions in cancer
Autoimmunity. 2014 Feb;47(1):46-56. doi: 10.3109/08916934.2013.850080. Epub 2013 Nov 5.
Superior anti-tumor protection and therapeutic efficacy of vaccination with dendritic cell/tumor cell fusion hybrids for murine Lewis lung carcinoma.
1Department of Cancer Biotherapy Center and.
The development of protocols for the ex vivo generation of dendritic cells (DCs) has led to intensive research into their potential use in immunotherapy in the treatment of cancer. In this study, we examined the efficacy of dendritic cell-tumor cell fusion hybrid vaccines in eliciting an immune response against Lewis lung carcinoma (LLC) cells, as compared to other types of tumor vaccines. In addition, we also tested whether the efficacy of the vaccines was affected by the route of administration. Four different tumor vaccines were compared: (1) HC (hybrid cell), consisting of DC/LLC hybrids; (2) DC+LLC (DCs pulsed with apoptotic LLCs); (3) DC without antigen loading/pulsing; (4) LLC (apoptotic/irradiated tumor cells). We also compared four different routes of administration for each vaccine: (1) Preimmunization; (2) Vaccination therapy; (3) Adoptive immunotherapy; (4) Vaccination therapy combined with adoptive immunotherapy. Anti-tumor immunity was assessed in vivo and the CTL (cytotoxic T lymphocyte) response as well as the expression of key cytokines, IFN-γ and IL-10 were further evaluated using in vitro assays.
Our data demonstrate that vaccination with HC hybrids provides more effective anti-tumor protective immunity and significantly greater therapeutic immunity than vaccination with DC+LLC, DC or LLC. Most remarkably, vaccination therapy with HC hybrids was more successful than combination (vaccination + adoptive) therapy for the induction of anti-tumor responses. Splenocytes harvested from mice immunized with HC hybrids demonstrated the greatest cytotoxic T lymphocyte (CTL) activity and their production of IFN-γ was high, while their production of IL-10 was very low.
Our results suggest that vaccination therapy with DC-tumor cell fusion hybrids provides more effective protection against lung cancer.
Keywords: Adoptive immunotherapy, cancer vaccine, dendritic cells, hybrids, Lewis lung carcinoma
Int Immunopharmacol. 2015 Apr;25(2):450-6. doi: 10.1016/j.intimp.2015.02.010. Epub 2015 Feb 16.
Dendritic cell immunotherapy combined with cytokine-induced killer cells promotes skewing toward Th2 cytokine profile in patients with metastatic non-small cell lung cancer.
1Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao 266042, China. Electronic address: firstname.lastname@example.org.
2The Affiliated Cardiovascular Hospital, Medical College of Qingdao University, Qingdao 266071, China.
3Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao 266042, China.
4Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital, Qingdao University Medical College, Qingdao 266042, China.
Dendritic cell (DC) vaccination and cytokine-induced killer (CIK) cell therapy (DC/CIK) have shown limited success in the treatment of advanced non-small cell lung cancer (NSCLC). To investigate the reason for this limited success, the effects of DC/CIK cell therapy on the immune responses of tumor-bearing patients and patients with resected NSCLC were evaluated. In the total 50 patients studied, the serum concentrations of the Th2 cytokines (IL-4 and IL-10) in tumor-bearing patients were significantly higher than those with resected NSCLC before immunotherapy. The post-therapy Th1 cytokine (IFN-γ) level in patients with resected NSCLC significantly increased from the pre-therapy level. In contrast, significantly enhanced post-therapy Th2 cytokine (IL-4 and IL-10) levels were found in tumor-bearing patients. The intracellular staining assay revealed that DC/CIK cell therapy increased the IFN-γ-producing T lymphocyte (CD8(+)IFN-γ(+)) frequency in patients with resected NSCLC, but these lymphocytes were not found in tumor-bearing patients. Furthermore, overproduction of vascular endothelial growth factor (VEGF) in tumor-bearing patients showed a statistically positive correlation with IL-4, suggesting that VEGF might be responsible for the predominance of serum Th2 cytokines. In a word, tumor-bearing patients developed a Th2-dominant status that could not be reversed toward Th1 following immunotherapy. A combined regiment of DC vaccination and CIK cell therapy with other treatments to overcome systemic Th2-dominant immune response might improve the current clinical benefit.
KEYWORDS: CIK cells; Dendritic cells; Immune response; Immunotherapy; Non-small cell lung cancer