Infiltration of the tumor microenvironment (TME) with cytotoxic T cells (CTLs) which recognize tumor-associated antigens (TAAs and TSAs) is required for the clinical efficacy of immunotherapy and for long-term effectiveness of chemo- and radiotherapies. Our group developed type-1-polarized dendritic cells (DC1) matured in the conditions of acute viral infections (dsRNA, type-1 and type-2 interferons) which selectively activate type-1 immunity and promote selective intratumoral entry of CTLs but not Tregs. Polarized DC1s show enhanced ability of DCs to cross-resent TAAs and induce DNAM1- and NKG2D-expressing CTLs which use these NK receptors to amplify weak TCR signals, enhancing the sensitivity and selectivity of recognition of cancer (but not healthy) cells which express both TAAs and NKR ligands.
Similar features can be induced in endogenous DCs by the “chemokine-modulatory” regimen (CKM) combining TLR3-ligand and IFN CKM selectively targets (NFB-high) cancer lesions, but not healthy tissues, allowing its systemic application to promote uniform CTL infiltration of multiple “cold” tumors. Our pilot trial NCT03403634 tested the safety and immunologic efficacy of systemic (i.v.) IFN2b and selective TLR3-ligand (rintatolimod/Ampligen) in patients with metastatic triple-negative breast cancer (TNBC). We observed very good tolerability, average of 10.3-fold increases in intratumoral CTL markers and preliminary indications of potential clinical activity. Analogous immunologic efficacy was observed on study NCT04081389 (neoadjuvant CKM plus chemotherapy in TNBC) and NCT02432378 (i.p. CKM plus chemotherapy in advanced ovarian cancer), with 7 of 9 patients displaying pathologic complete responses (pCR) or microscopic disease at the time of tumor resection, known to predict positive long-term outcomes. 
Our upcoming trials will test combinations of CKM and DC therapies with immune checkpoint inhibitors (ICI) and adoptive T cell therapies (ACT).
Supported by NIH/NCI grants (P01CA132714, P01CA234212, P30A016056, P50CA159981, K08CA279766), NIH/NCATS grants (UL1TR001412, KL2TR001413, R03TR004607), DOD grant W81XWH-19-1-0674, and grants from the Pittsburgh Foundation, Jacobs Family Foundation, Rustum Foundation, Roswell Park Alliance Foundation and Roswell Park Institutional Funds.

Learning Objectives:

1. Describe how type-1–polarized dendritic cells (αDC1) enhance CTL activation and tumor recognition compared to conventional DCs.

2. Explain how chemokine-modulatory regimens (CKM) promote endogenous DC activation and cytotoxic T cell infiltration in “cold” tumors.

3. Discuss recent clinical trial outcomes using DC-based and CKM approaches in combination therapies for triple-negative breast and ovarian cancers.