Combinational immunotherapy including intratumoral administration of autologous myelid dendretic cells for solid tumors

Although treatment with immune checkpoint blockers (ICB) such as the antiprogrammed cell death protein 1 (PD-1) monoclonal antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab can induce durable remissions, most patients with advanced melanoma will not respond to this treatment from the beginning or will develop resistance during therapy. Melanoma patients without BRAF-mutation, approximately half of the patients, lack additional treatment options in case of absent targetable BRAF mutation and therefore have a somber prognosis. Intratumoral (IT) myeloid dendritic cells (myDCs) are pivotal in initiating antitumor immune responses and relicensing antitumor cytotoxic T lymphocytes within the tumor microenvironment (TME). The main objective of this doctoral thesis was to establish a “non-advanced therapy medicinal product” cellular treatment approach based on the IT injection of autologous, non-substantially manipulated myDCs isolated from the blood in combination with immunotherapeutic agents such as ICB or oncolytic virus to reinvigorate the cancer-immunity cycle, and to evaluate the safety, and feasibility of such an approach as well as potential antitumor activity. Another objective throughout the different studies was to understand better the cellular and molecular changes in the TME upon study treatment. We performed molecular and cellular analysis of baseline and when indicated, on-treatment tumor biopsies in search of biomarkers.
In a phase II trial in patients with fully resected melanoma, we investigated two lowdose schemes of nivolumab with or without a single administration of low-dose ipilimumab as an adjuvant therapy. A less frequent dosing scheme with a fixed dose of nivolumab 10 mg intravenously administered lead to survival and incidence of treatment-related adverse events comparable to standard dosing. Low doses of ICB, used as a treatment backbone, could be of interest for clinical trials investigating combinations with other immunotherapeutic agents such as DC therapies.
In a first-in-human study for patients with advanced solid tumors, we investigated IT injection of autologous, unmanipulated CD1c (BDCA-1)+ myDCs in combination with IT injection of ipilimumab and the anti-PD-L1 antibody avelumab plus intravenous administration of low-dose nivolumab. As ipilimumab and avelumab are IgG1 monoclonal antibodies, the IT injection of these antibodies might induce antibodydependent cellular cytotoxicity and complement-dependent cytotoxicity, thereby releasing tumor antigens, creating an inflamed TME in which co-injected myDCs could mature and get activated. In a second phase I trial, IT administration of autologous, unmanipulated CD1c (BDCA-1)+ myDCs with or without CD141 (BDCA-3)+ myDCs in combination with the Herpes simplex virus type I-derived oncolytic virus talimogene laherparepvec (T-VEC) was investigated. T-VEC is believed to create an inflamed TME, preparing the TME for maturation and activation of co-injected myDCs. Both strategies were feasible and safe, and in both trials promising clinical responses in patients who previously progressed on standard therapies including ICB have been observed.
Available ICB therapies are largely ineffective for patients with glioblastoma, the most malignant primary brain tumor. Our research group initiated an adaptive, multi-cohort phase I clinical trial (Glitipni) in patients with recurrent glioblastoma. Here, I report on the results of the cohorts in which we investigated the intracerebral administration of ipilimumab with or without nivolumab (cohort-1/-2) plus CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDCs (cohort-5/-6) in combination with intravenous low-dose nivolumab in patients with resectable glioblastoma recurrence after maximal safe surgical resection. The treatment was feasible and safe, and we observed some early signs of antitumor activity.
Overall, IT injection of autologous, non-substantially manipulated myDCs isolated from the blood in combination with immunotherapeutic agents seems promising but needs further investigation.