Immune checkpoint inhibitors targeting programmed cell death protein 1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated protein 4 provide deep and durable treatment responses which have revolutionized oncology. However, despite over 40% of cancer patients being eligible to receive immunotherapy, only 12% of patients gain benefit. A key to understanding what differentiates treatment response from non-response is better defining the role of the innate immune system in anti-tumor immunity and immune tolerance. Teleologically, myeloid cells, including macrophages, dendritic cells, monocytes, and neutrophils, initiate a response to invading pathogens and tissue repair after pathogen clearance is successfully accomplished. However, in the tumor microenvironment (TME), these innate cells are hijacked by the tumor cells and are imprinted to furthering tumor propagation and dissemination. Major advancements have been made in the field, especially related to the heterogeneity of myeloid cells and their function in the TME at the single cell level, a topic that has been highlighted by several recent international meetings including the 2021 China Cancer Immunotherapy workshop in Beijing. Here, we provide an up-to-date summary of the mechanisms by which major myeloid cells in the TME facilitate immunosuppression, enable tumor growth, foster tumor plasticity, and confer therapeutic resistance. We discuss ongoing strategies targeting the myeloid compartment in the preclinical and clinical settings which include: (1) altering myeloid cell composition within the TME; (2) functional blockade of immune-suppressive myeloid cells; (3) reprogramming myeloid cells to acquire pro-inflammatory properties; (4) modulating myeloid cells via cytokines; (5) myeloid cell therapies; and (6) emerging targets such as Siglec-15, TREM2, MARCO, LILRB2, and CLEVER-1. There is a significant promise that myeloid cell-based immunotherapy will help advance immuno-oncology in years to come.

Background Severe hypercalcemia is often associated with uncontrolled malignancy through several mechanisms. However, calcitriol-mediated hypercalcemia is a rare etiology for advanced solid tumors. Case presentation We report a case of calcitriol-mediated hypercalcemia secondary to immune checkpoint inhibition in a responder with metastatic clear cell renal cell carcinoma (ccRCC). In this case, a 68 year old male with metastatic ccRCC to the liver within 4 months of right radical nephrectomy went on to develop hypercalcemia (12.8 mg/dL) shortly following 2 cycles of nivolumab and ipilimumab. Additional testing showed an elevated calcitriol level (142 pg/mL), low parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) levels, and a normal 25-hydroxyvitamin D level. FDG-PET imaging showed hypermetabolic mediastinal, hilar, and intra-abdominal lymphadenopathy, however the subsequent lymph node biopsy only showed reactive lymphoid cells without malignancy or granuloma. The hypercalcemia was resistant to initial therapy with calcitonin, hydration, and zoledronic acid but quickly responded to high-dose prednisone (1 mg/kg), followed by normalization of calcitriol levels. The patient was rechallenged with nivolumab and ipilimumab which provided a partial response after 4 cycles. He was maintained on low dose prednisone (10 mg daily) leading to a sustained resolution of his hypercalcemia. Conclusion This case suggests calcitriol-mediated hypercalcemia as a novel immune-related adverse event.

Introduction The immunomodulatory impact of corticosteroids and concurrent chemotherapy is poorly understood within triple-negative breast cancer (TNBC). On a biochemical level, steroids have been linked to the signaling of chemotherapy-resistant pathways. However, on a clinical level, steroids play an essential role in chemotherapy tolerance through the prevention of chemotherapy-induced nausea and vomiting (CINV) and hypersensitivity reactions. Given these conflicting roles, we wanted to evaluate this interplay more rigorously in the context of early-stage TNBC. Methods We performed a retrospective analysis of patients with operable TNBC who received neoadjuvant chemotherapy (NAC) between January 2012 and November 2018, with the primary goal of examining the dose-dependent relationship between pathological complete response (pCR) rates and corticosteroid use. Secondary endpoints included the impact of steroid dosing on overall survival (OS) and recurrence-free survival (RFS), along with a breakdown in pCR rates based on steroid doses provided during each chemotherapy phase. Further adjusted analyses were performed based on patient age, diabetic status, and anatomical stage. Finally, we explored the relationship between tumor-infiltrating lymphocytes (TILs) seen on tissue samples at baseline and dexamethasone doses in terms of pCR rates. Results In total, of the 174 patients screened within this study period, 116 met full eligibility criteria. Of these eligible patients, all were female, with a median age of 51.5 years (27.0 to 74.0) and a mean body mass index (BMI) of 29.7 [standard deviation (SD) 7.04]. The majority were nondiabetic (80.2%). For cancer stage, 69.8% ( n = 81) had stage 2 breast cancer. We found no statistically significant association between pCR rates and dexamethasone use, both in terms of the total dose ( p = 0.55) and mean dose per NAC cycle ( p = 0.74). Similarly, no difference was noted when adjusting for diabetic status, metformin use, or age at diagnosis, regardless of the total steroid dose provided ( p = 0.72) or mean dose per cycle ( p = 0.49). No meaningful changes to pCR rate were seen with higher mean or higher total steroid doses during the paclitaxel (T) phase (adjusted p = 0.16 and p = 0.76, respectively) or doxorubicin and cyclophosphamide (AC) phase (adjusted p = 0.83 and p = 0.77, respectively). Furthermore, we found no clinically significant association between dexamethasone dose and either RFS ( p = 0.45) or OS ( p = 0.89). Of the 56 patients who had available pre-treatment biopsy tissue samples, 27 achieved pCR, with higher TILs at baseline being associated with higher pCR rates, regardless of the mean de...

532 Background: Limited compelling prospective and retrospective data regarding the added benefit of anti-HER2 therapy in the management of small, node-negative HER2-positive breast cancer (HER2+BC) exists, in part due to differences in outcome reporting, unmatched analyses, and a lack of head-to-head comparisons. As a result, national guideline committees find themselves unable to confidently recommend anti-HER2 therapy and clinicians are left to exercise clinical judgement on whether the use of anti-HER2 therapy should be considered for such patients. Methods: Our team performed a multi-institutional retrospective analysis using the ASCO CancerLinQ database, with a focus on clinical data from small, node-negative HER2+BC patients diagnosed between 2010 to 2021. We compared clinical outcomes between those who received adjuvant trastuzumab therapy, with or without chemotherapy, to those who did not, with our primary outcomes being invasive disease-free survival (iDFS) and overall survival (OS). We performed both a univariate and multivariate analysis, using a Cox proportional hazard model to control for factors including age, ethnicity, body mass index, hormone status, tumor grade, histology type, BRCA status, region, and smoking history. Additionally, a three-arm univariate analysis was performed comparing untreated patients to trastuzumab alone versus combination therapy. Results: In total, 1206 patients met inclusion criteria, including 779 patients who received trastuzumab with or without chemotherapy. We found a statistically significant improvement in both iDFS (HR 0.73, p = 0.01) and OS (HR 0.63, p = 0.027) on univariate analysis for those receiving anti-HER2 therapy. Similarly on multivariate analysis, iDFS (HR 0.75, p = 0.030) and OS (HR 0.61, p = 0.029) were improved in those who received therapy, regardless of tumor size. Our three-arm univariate analysis involving no treatment (n = 427), trastuzumab monotherapy (n = 169), and combination therapy (n = 578) found that iDFS was significantly improved for both treatment arms compared to observation alone (p = 0.006), whereas OS trended towards significance in the treatment arms but did not reach this target (p = 0.061). No significant difference was noted between treatment arms. Conclusions: Our analysis found a statistically significant improvement in iDFS and OS when patients with small, node negative, HER2+BC received adjuvant anti-HER2 therapy with or without chemotherapy as compared to observation. From our univariate three-arm comparison, it appears that trastuzumab provides the majority of benefit to patients in terms of DFS, but this result is exploratory. Further investigation is warranted, including meta-analyses to better characterize the degree of benefit seen with anti-HER2 treatment. For now, this data adds to evidence suggesting added benefit with therapy over observation.