Abstract 2499: Clinical and immunopathological effects following Image-guided intratumoral injection of activated, autologous dendritic cells in patients with advanced solid cancers
Authors: Subbiah Vivek , Murthy Ravi , Hong David S. , Brown Robert E. , Prins Robert , Hosing Chitra , McGuire Mary , Naing Aung , Fu Siquing , Chou Tina , Lin Quan , Guevarra Richard P. , Conley Anthony , Kaur Indreshpal , Meric-Bernstam Funda , Bosch Marnix 
Published: August 2015

Introduction: Preclinical models have shown that activated DC's can effectively clear both injected (local) and non-injected (distal) inoperable tumor lesions. Based on this strong rationale a Phase I trial was designed to exploit this finding in late stage solid tumors.

Methods: We designed a phase I study to determine the safety of intratumoral injection of activated DC by administering the product repeatedly until disease progression or unacceptable toxicity, in advanced cancers. Endpoints included maximum tolerated (MTD), dose limiting toxicities (DLT), safety, and immune response criteria (iRC) and RECIST. The treatment consisted of image-guided intratumoral (IT) injections of autologous, activated dendritic cells (DCVax-Direct,). Injections were given on days 0, 7 and 14, followed by booster immunizations at weeks 4, 8 and 16. Three dose levels, at 2 million, 6 million or 15 million DC per injection, were tested. Concomitant, serial biopsies were performed at the time of the vaccination in the absence of toxicity /progression. Systemic immune responses were tracked through evaluation of T cell subsets and cytokines in circulation, and through T cell receptor (TCR) sequencing in the tumor tissue and in the periphery.

Results: To date, 40 patients (men, n = 18; women, n = 22), median age 53.7 (range 30 - 73) years, median of 3.1 (1 - 6) prior therapies (including 1 patient with prior immune therapy) were enrolled. Seventeen patients were treated at the 2 million dose level, 19 at the 6 million dose level, and 3 at 15 million. The MTD has not been reached and there were no dose limiting toxicities. Two patients experienced Grade 3/4 drug related toxicities : one case of fever and dehydration and one case of systemic inflammatory response syndrome. Patterns of immunological reactivity were assessed by pathological scoring on tumor biopsies for 29 patients, and included increasing necrosis in 62% of patients and emergence or amplification of infiltrating T cells in 55%. In-depth study was carried out in a patient with therapy-refractory, de-differentiated liposarcoma whose imaging at 12 weeks post initial injection revealed necrosis in the primary tumor and stable lung metastases. Biopsies demonstrated an intra-tumoral inflammatory response consisting of lymphocytes, macrophages and TIA-1 expressing cells, suggesting cytolytic activity. TCR sequencing revealed the presence of shared TCR sequences in the tumor as well as in circulation, demonstrating a systemic anti-tumor response. Analysis of T cell subsets in circulation demonstrated normalization of the CD4/CD8ratio.

Conclusion:

Immunotherapy with partially activated DC's injected IT demonstrate early signals of immune reactivity even in late stage patients with cancer. Preliminary data support the generation of anti-tumor effects following IT injection of the partially activated, autologous DC’s.

Citation Format: Vivek Subbiah, Ravi Murthy, David S. Hong, Robert E. Brown, Robert Prins, Chitra Hosing, Mary McGuire, Aung Naing, Siquing Fu, Tina Chou, Quan Lin, Richard P. Guevarra, Anthony Conley, Indreshpal Kaur, Funda Meric-Bernstam, Marnix Bosch. Clinical and immunopathological effects following Image-guided intratumoral injection of activated, autologous dendritic cells in patients with advanced solid cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2499. doi:10.1158/1538-7445.AM2015-2499