Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer

etuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m2 and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9–11.4) and 8.9 (90% CI = 2.7–15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6–40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8+ subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC

Early Myeloid Dendritic Cell Dysregulation is Predictive of Disease Progression in Simian Immunodeficiency Virus Infection

Myeloid dendritic cells (mDC) are lost from blood in individuals with human immunodeficiency virus (HIV) infection but the mechanism for this loss and its relationship to disease progression are not known. We studied the mDC response in blood and lymph nodes of simian immunodeficiency virus (SIV)-infected rhesus macaques with different disease outcomes. Early changes in blood mDC number were inversely correlated with virus load and reflective of eventual disease outcome, as animals with stable infection that remained disease-free for more than one year had average increases in blood mDC of 200% over preinfection levels at virus set-point, whereas animals that progressed rapidly to AIDS had significant loss of mDC at this time. Short term antiretroviral therapy (ART) transiently reversed mDC loss in progressor animals, whereas discontinuation of ART resulted in a 3.5-fold increase in mDC over preinfection levels only in stable animals, approaching 10-fold in some cases. Progressive SIV infection was associated with increased CCR7 expression on blood mDC and an 8-fold increase in expression of CCL19 mRNA in lymph nodes, consistent with increased mDC recruitment. Paradoxically, lymph node mDC did not accumulate in progressive infection but rather died from caspase-8-dependent apoptosis that was reduced by ART, indicating that increased recruitment is offset by increased death. Lymph node mDC from both stable and progressor animals remained responsive to exogenous stimulation with a TLR7/8 agonist. These data suggest that mDC are mobilized in SIV infection but that an increase in the CCR7-CCL19 chemokine axis associated with high virus burden in progressive infection promotes exodus of activated mDC from blood into lymph nodes where they die from apoptosis. We suggest that inflamed lymph nodes serve as a sink for mDC through recruitment, activation and death that contributes to AIDS pathogenesis

Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

High ERβ/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma

Differential activation of blood mDC in stable and progressive SIV infection.

<p>The proportion of blood mDC expressing CCR7 (A), CD80 (B) and CD86 (C) relative to staining with a control antibody before and at various times after SIV infection. Shown are mean ± SEM for naïve (n = 19), progressor (n = 8) and stable animals (n = 10). (D) Representative flow cytometry plots of the gating strategy to identify positive populations. (E) Flow cytometry plots of CCR7⁺ mDC from progressor animal R180 at 12 weeks post infection labeled with antibodies to CD80 and CD86. Numbers represent the percentage of cells that co-express both markers relative to staining with a control antibody. Data are representative of three experiments on separate animals. *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.005 between groups; #<i>P</i><0.05, ##<i>P</i><0.01, ###<i>P</i><0.005 within groups relative to week 0. ART = interval of antiretroviral therapy.</p

HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString’s nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population

Lymph node mDC from SIV infected animals remain responsive to exogenous TLR8 stimulation.

<p>The proportion of lymph node mDC before and after SIV infection that express (A) TNF-α (A) or IL-12 (B) following stimulation with the TLR7/8 agonist 3M-007 for 5 hours. Shown are mean ± SEM for naïve (T = 0, n = 13), progressor (n = 7) and stable animals (n = 10). Also shown are representative flow cytometry plots of the gating strategy to identify positive populations. #<i>P</i><0.05, ##<i>P</i><0.01 within groups relative to week 0. ART = interval of antiretroviral therapy.</p

Divergent mDC response in blood correlates with virus load and disease progression.

<p>(A) Representative flow cytometry plots showing the gating strategy used to define CD11c⁺ mDC within the Lineage⁻ HLA-DR⁺ fraction of PBMC. (B) Changes in the absolute number of mDC in blood over the course of SIV infection in animals with stable (n = 10) and progressive (n = 9) infection. Shown are mean ± SEM. **<i>P</i><0.01 between groups; #<i>P</i><0.05; ##<i>P</i><0.01 within groups relative to week 12 post infection. (C, D) Individual mDC counts in blood for progressor animals (C, n = 9) and stable animals (D, n = 10). (E) Correlation between percent change of mDC in blood from week 0 to 12 and virus load at week 12 (n = 18, R189 died at week 11 and is not included). (F) Change in absolute number of CD4 T cells in blood over the course of SIV infection in animals with stable (n = 10) and progressive (n = 9) infection. Shown are mean ± SEM. ART = intervals of antiretroviral therapy.</p

Characteristics of animal cohort.

<p>*Expression of known MHC class I Mamu alleles. ND = none of the 8 alleles tested was expressed.</p>¶<p>Immunotherapy was administered at weeks 16 and 22 for Ad5-based vectors and weeks 36 and 42 for Ad35-based vectors. Control = Ad-ψ5; Ad-SIV = separate vectors expressing SIV Env, Gag and Nef; Ad-SIV/IL-15 = separate vectors expressing SIV Env, Gag, Nef and IL-15.</p>†<p>Mean values from week 8–12 post infection.</p>‡<p>Animals in the stable group were electively sacrificed at or after 56 weeks post infection (PI). Animals in the progressor group were sacrificed due to development of AIDS at the indicated times.</p