Thursday, March 10, 2016

Dendritic cell vaccines. Perhaps this approach will allow vaccines to live up to their potential for melanoma....SOON!!!

Effective clinical responses in metastatic melanoma patients after vaccination with primary myeloid dendritic cells.  Screibelt, Westdorp, Wimmers, et al.  Clin Cancer Res. 2015 Dec 28.

Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocyte-derived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c+ myeloid DCs, naturally circulating in the blood. Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c+ myeloid DCs, activated by only brief (16h) ex vivo culture and loaded with tumor associated antigens of tyrosinase and gp100. Our results show that therapeutic vaccination against melanoma with small amounts (3-10x106) of myeloid DCs is feasible and without substantial toxicity. Four out of fourteen patients showed long-term progression-free survival (12-35 months), which directly correlated with the development of multifunctional CD8+ T cell responses in three of these patients. In particular, high CD107a expression, indicative for cytolytic activity, and IFNγ as well as tumor necrosis factor (TNF)α and CCL4 production was observed. Apparently, these T cell responses are essential to induce tumor regression and promote long-term survival by stalling tumor growth. We show that vaccination of metastatic melanoma patients with primary myeloid DCs is feasible and safe and results in induction of effective anti-tumor immune responses that coincide with improved progression-free survival.

A phase I/IIa clincal trial in Stage IV melanoma of an autologous tumor-dendritic cell fusion (dendritoma) vaccine with low dose interleukin-2.  Greene, Schneble, Jackson, et al. Cancer Immunol Immunother. 2016 Feb 19.

Stage IV melanoma has high mortality, largely unaffected by traditional therapies. Immunotherapy including cytokine therapies and checkpoint inhibitors improves outcomes, but has significant toxicities. In this phase I/IIa trial, we investigated safety and efficacy of a dendritoma vaccine, an active, specific immunotherapy, in stage IV melanoma patients.
Autologous tumor lysate and dendritic cells were fused creating dendritoma vaccines for each patient. Phase I patients were vaccinated every 3 months with IL-2 given for 5 days after initial inoculation. Phase IIa patients were vaccinated every 6 weeks with IL-2 given on days 1, 3 and 5 after initial inoculation. Toxicity and clinical outcomes were assessed.
Twenty-five patients were enrolled and inoculated. All dendritoma and IL-2 toxicities were The dendritoma vaccine has minimal toxicity profile with potential clinical benefit. There was OS advantage for NED stage IV patients, those receiving higher number of doses and increased frequency. Based on these results, we initiated a phase IIb trial utilizing improved dendritoma technology in the adjuvant setting for NED stage III/IV melanoma patients.

Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination.  Bol, Aarntzen, Hout, et al.  Oncoimmunology. 2015 Jun 5.

Melanoma patients with regional metastatic disease are at high risk for recurrence and metastatic disease, despite radical lymph node dissection (RLND). We investigated the immunologic response and clinical outcome to adjuvant dendritic cell (DC) vaccination in melanoma patients with regional metastatic disease who underwent RLND with curative intent. In this retrospective study, 78 melanoma patients with regional lymph node metastasis who underwent RLND received autologous DCs loaded with gp100 and tyrosinase and were analyzed for functional tumor-specific T cell responses in skin-test infiltrating lymphocytes. The study shows that adjuvant DC vaccination in melanoma patients with regional lymph node metastasis is safe and induced functional tumor-specific T cell responses in 71% of the patients. The presence of functional tumor-specific T cells was correlated with a better 2-year overall survival (OS) rate. OS was significantly higher after adjuvant DC vaccination compared to 209 matched controls who underwent RLND without adjuvant DC vaccination, 63.6 mo vs. 31.0 mo. Five-year survival rate increased from 38% to 53%. In summary, in melanoma patients with regional metastatic disease, who are at high risk for recurrence and metastatic disease after RLND, adjuvant DC vaccination is well tolerated. It induced functional tumor-specific immune responses in the majority of patients and these were related to clinical outcome. OS was significantly higher compared to matched controls. A randomized clinical trial is needed to prospectively validate the efficacy of DC vaccination in the adjuvant setting.

Thanks, Ratties!!! - c

No comments:

Post a Comment