Abstract B005: Cytokine production by intratumorally administered activated dendritic cells correlates with survival in a Phase I clinical trial in diverse cancers
Authors: Subbiah Vivek , Murthi Ravi , Prins Robert , Hendricks Kyle , Hosing Chitra , Noffsinger Lori , McGuire Mary , Brown Robert , Naing Aung , Hong David , Fu Siqing , Conley Anthony , Kaur Indreshpal , Campion Sarah , Bosch Marnix 
Published: November 2016

Abstract
Background: Activated, autologous dendritic cells (aaDC) can be used to induce anti-tumor immune responses. A unique method of applying aaDC is through intratumoral injection, where the tumor cells serve as the source of antigen required for an adaptive anti-tumor response. A local effect may also occur as a result of cytokine production by the injected DC which makes the tumor more susceptible to a pre-existing or an induced immune attack.
Methods: Forty patients with locally advanced or metastatic solid tissue cancers were treated in a dose escalation trial in which aaDC were injected percutaneously under image guidance into a single tumor. Subjects had a median of 3 tumors (range 1 - 5) and had received an average of 3.1 prior treatments. To generate the aaDC, autologous monocytes were converted ex vivo into DC which were then activated. All batches of DC were released based on pre-specified criteria which included immunophenotyping and a T cell-stimulation assay, as well as sterility and endotoxin levels. Cytokine levels produced by the activated DC during manufacturing were measured and patient outcomes were correlated to these expression levels.
Results: All three doses levels were well tolerated. The main adverse events related to treatment were grade 1 and 2 fevers. Twenty-one patients achieved stable disease (SD) 8 weeks after initiating treatment, and this was found to correlate with survival (p = 0.01). Levels of certain cytokines, such as such IL-8 and IL-12 p40, and TNFα were substantially elevated in vitro and IL-8 and IL-12 p40 production were predictive of survival (p = 0.001 and p = 0.008 resp.). TNFα levels also correlated with SD at week 8 (p = 0.01). More than 70% of patients tested were found to have significant T cell responses, and/or de novo or significantly enhanced PD-L1 expression in the tumor post treatment, with a trend towards improved survival (p = 0.1).
Conclusions: Study outcomes such as stabilization of disease and survival correlated with high DC cytokine levels, in the absence of meaningful toxicity. The DCVax treatment may be mediated through direct cytotoxic effects, as well as modulation of the tumor microenvironment to increase tumor infiltration by T cells, and attraction of inflammatory cells to the tumor. The development of PD-L1 expression likely reflects an induced immune response.
Citation Format: Vivek Subbiah, Ravi Murthi, Robert Prins, Kyle Hendricks, Chitra Hosing, Lori Noffsinger, Mary McGuire, Robert Brown, Aung Naing, David Hong, Siqing Fu, Anthony Conley, Indreshpal Kaur, Sarah Campion, Marnix Bosch. Cytokine production by intratumorally administered activated dendritic cells correlates with survival in a Phase I clinical trial in diverse cancers [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B005.