Highly Active Myeloid Therapy for Cancer

Abstract

Tumor-associated macrophages (TAM) interact with cancer and stromal cells and are integral to sustaining many cancer-promoting features. Therapeutic manipulation of TAM could therefore improve clinical outcomes and synergize with immunotherapy and other cancer therapies. While different nanocarriers have been used to target TAM, a knowledge gap exists on which TAM pathways to target and what payloads to deliver for optimal antitumor effects. We hypothesized that a multipart combination involving the Janus tyrosine kinase (JAK), noncanonical nuclear factor kappa light chain enhancer of activated B cells (NF-κB), and toll-like receptor (TLR) pathways could lead to a highly active myeloid therapy (HAMT). Thus, we devised a screen to determine drug combinations that yield maximum IL-12 production from myeloid cells to treat the otherwise highly immunosuppressive myeloid environments in tumors. Here we show the extraordinary efficacy of a triple small-molecule combination in a TAM-targeted nanoparticle for eradicating murine tumors, jumpstarting a highly efficient antitumor response by adopting a distinctive antitumor TAM phenotype and synergizing with other immunotherapies. The HAMT therapy represents a recently developed approach in immunotherapy and leads to durable responses in murine cancer models.

Pharmacological Polarization of Tumor‐Associated Macrophages Toward a CXCL9 Antitumor Phenotype

“…We had previously developed a cyclodextrin‐adjuvant nanoparticle‐drug delivery system (CANDI) that accumulates avidly in TAM after systemic injection and enables highly effective, multitarget, and pathway modulation inside TAM and dendritic cells. [ 9 , 14 ] Specifically, versions of this delivery platform had primarily been used to induce IL12 in TAM. [ 14 ] Unfortunately, the prior drug combination “HAMT” (LCL161, R848, and Ruxolitinib) had no effect on cellular CXCL9 expression (Figure 3 ).…”

“…[ 9 , 14 ] Specifically, versions of this delivery platform had primarily been used to induce IL12 in TAM. [ 14 ] Unfortunately, the prior drug combination “HAMT” (LCL161, R848, and Ruxolitinib) had no effect on cellular CXCL9 expression (Figure 3 ). [ 14 ]…”

“…[ 14 ] Unfortunately, the prior drug combination “HAMT” (LCL161, R848, and Ruxolitinib) had no effect on cellular CXCL9 expression (Figure 3 ). [ 14 ]…”

“…[ 9 , 10 , 11 , 13 ] Unfortunately, the prior formulations showed no CXCL9 up‐regulation. [ 14 ] The chemokine CXCL9 promotes antitumor lymphocytic infiltration in solid tumors via its receptor CXCR3. Its production in TAM is believed to be mostly regulated by interferon‐gamma (IFNg) stimulation and signal transducer and activator of transcription 1 (STAT1) pathway [ 15 , 16 ] but possibly also by other pathways (e.g., Toll‐Like Receptor (TLR) via Nuclear Factor kΒ (NFkB), [ 17 ] Stimulator of Interferon Genes (STING), [ 18 ] and Poly‐ADP‐ribose polymerase 7 (PARP7), a member of the monoPARP family, key regulator of stress response and IFNg secretion).…”

A non-lipid nucleic acid delivery vector with dendritic cell tropism and stimulation

“…Particle synthesis. We synthesized b-s-CD de novo with a defined degree of substitution (DS) of either 2 or 3 succinyl groups per CD (average DS of 2.5) 33 , 45 . This degree of substitution is narrower than in commercially available products, in which we had observed much broader substitutions ranging from 1-5 succinyls per CD.…”