Human CD22-Transgenic, Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments

Targeted immunotherapies have greatly changed treatment of patients with B cell malignancies. To further enhance immunotherapies, research increasingly focuses on the tumor microenvironment (TME), which differs considerably by organ site. However, immunocompetent mouse models of disease to study immunotherapies targeting human molecules within organ-specific TME are surprisingly rare. We developed a myc-driven, primary murine lymphoma model expressing a human-mouse chimeric CD22 (h/mCD22). Stable engraftment of three distinct h/mCD22+ lymphoma was established after subcutaneous and systemic injection. However, only systemic lymphoma showed immune infiltration that reflected human disease. In this model, myeloid cells supported lymphoma growth and showed a phenotype of myeloid-derived suppressor cells. The human CD22-targeted immunotoxin Moxetumomab was highly active against h/mCD22+ lymphoma and similarly reduced infiltration of bone marrow and spleen of all three models up to 90-fold while efficacy against lymphoma in lymph nodes varied substantially, highlighting relevance of organ-specific TME. As in human aggressive lymphoma, anti-PD-L1 as monotherapy was not efficient. However, anti-PD-L1 enhanced efficacy of Moxetumomab suggesting potential for future clinical application. The novel model system of h/mCD22+ lymphoma provides a unique platform to test targeted immunotherapies and may be amenable for other human B cell targets such as CD19 and CD20.

Pathology Quality Control for Multiplex Immunofluorescence and Image Analysis Assessment in Longitudinal Studies

Immune profiling of formalin-fixed, paraffin-embedded tissues using multiplex immunofluorescence (mIF) staining and image analysis methodology allows for the study of several biomarkers on a single slide. The pathology quality control (PQC) for tumor tissue immune profiling using digital image analysis of core needle biopsies is an important step in any laboratory to avoid wasting time and materials. Although there are currently no established inclusion and exclusion criteria for samples used in this type of assay, a PQC is necessary to achieve accurate and reproducible data. We retrospectively reviewed PQC data from hematoxylin and eosin (H&E) slides and from mIF image analysis samples obtained during 2019. We reviewed a total of 931 reports from core needle biopsy samples; 123 (13.21%) were excluded during the mIF PQC. The most common causes of exclusion were the absence of malignant cells or fewer than 100 malignant cells in the entire section (n = 42, 34.15%), tissue size smaller than 4 × 1 mm (n = 16, 13.01%), fibrotic tissue without inflammatory cells (n = 12, 9.76%), and necrotic tissue (n = 11, 8.94%). Baseline excluded samples had more fibrosis (90 vs 10%) and less necrosis (5 vs 90%) compared with post-treatment excluded samples. The most common excluded organ site of the biopsy was the liver (n = 19, 15.45%), followed by soft tissue (n = 17, 13.82%) and the abdominal region (n = 15, 12.20%). We showed that the PQC is an important step for image analysis and that the absence of malignant cells is the most limiting sample characteristic for mIF image analysis. We also discuss other challenges that pathologists need to consider to report reliable and reproducible image analysis data.

Secondary Breast Cancer Sociodemographic Characteristics and Survival by Age Group

Background Secondary cancers account for 16% of all new cancer diagnoses, with breast cancer (BC) the most common secondary cancer. We have shown that secondary BC has unique characteristics and decreased survival compared with primary BC in adolescent and young adults (AYA; 15–39 years old). However, older BC populations are less well studied. Methods Females (age ≥ 15 years) diagnosed with primary BC during 1991–2015 (n = 377,167) and enrolled in the California Cancer Registry were compared with those with secondary BC (n = 37,625) by age (15–39, 40–64, ≥ 65 years). We examined BC-specific survival (BCSS) accounting for other causes of death as a competing risk using multivariable Cox proportional hazards regression. Results Most secondary BC patients were of older age (15–39, n = 777; 40–64, n = 15,848; ≥ 65, n = 21,000). Compared with primary BC treatment, secondary BCs were more often treated with mastectomy and less often with chemotherapy and/or radiation. BCSS was shorter in secondary BC patients than primary BC patients, but the survival difference between secondary and primary BC diminished with age [15–39 hazard ratio (HR): 2.09, 95% confidence interval (CI) 1.83–2.39; 40–64 HR: 1.51; 95% CI 1.44–1.58; ≥ 65 HR: 1.14; 95% CI 1.10–1.19]. Survival differences were most pronounced in women with hormone receptor positive disease and Hispanic and Asian/Pacific Islanders 40–64 years of age. Conclusions When BC is diagnosed following a prior cancer of any organ site, BCSS is worse than when compared with patients for whom BC is the primary diagnosis, suggesting that we may need to tailor our treatments for women with secondary BC.

Phase I study investigating the safety of stereotactic body radiotherapy (SBRT) with anti-PD-1 and anti-IL-8 for the treatment of multiple metastases in advanced solid tumors.

TPS2681 Background: Anti-PD-(L)1 immunotherapy improves outcomes for patients across various cancers; however, many patients do not benefit. Previous studies combining multi-site SBRT with anti-PD1 have confirmed feasibility and revealed induction of interferon signaling by SBRT. Elevated levels of serum IL8 (sIL8) associate with lack of response to anti-PD1 and we have observed that elevated IL8 is strongly associated with lack of response to immunotherapy and SBRT combinations. Overcoming IL8 induced epithelial-mesenchymal transitioning and trafficking of myeloid derived suppressor cells in tumor microenvironment therefore represents a promising strategy to overcome resistance. BMS-986253 is a fully human neutralizing antibody that binds to sIL8. The combination of BMS-986253 and nivolumab was safe in patients with advanced solid tumors. The present study aims to evaluate safety and preliminary efficacy of combining BMS-986253 with nivolumab and SBRT in patients with advanced solid tumors, Melanoma (MEL) and Renal Cell Carcinoma (RCC). Methods: This is a phase 1 open label single arm study (CT.gov: NCT04572451) which will include safety and efficacy cohorts. Patients will receive SBRT in 1-4 tumor lesions, in 3 or 5 fractions, at the total of 30 or 45 or 50 Gy based on the irradiated organ site. This will be followed by intravenous (IV) nivolumab (480mg q4 weeks (W)) and IV BMS-986253 (2400mg q2W) within seven days of completing SBRT. In the initial safety portion of the clinical trial, we will include 30 patients with advanced/metastatic solid tumors in order to evaluate safety. The primary endpoint of dose limiting toxicity will be assessed by continual Bayesian monitoring. The toxicities will be attributed to combination of SBRT/Immunotherapy as opposed to individual components. The secondary objective of the study is efficacy with an endpoint of objective response rate (ORR) as assessed by RECIST v1.1 in Mel and RCC. We will include 20 patients with MEL and RCC and compare against a historical benchmark of 20% ORR as sufficient signal of activity for further study. ORR will be assessed for association with serum IL-8 levels and radiation-induced changes in peripheral blood T cell populations. Clinical trial information: NCT04572451.

New insights into patterns of first metastatic sites influencing survival of patients with hormone receptor-positive, HER2-negative breast cancer: a multicenter study of 271 patients

Background The initial therapeutic strategy for hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer is based on the first metastatic site; however, little evidence is available regarding the influence of metastatic distribution patterns of first metastatic sites on prognosis. In this study, we aimed to identify the metastatic distribution patterns of first metastatic sites that significantly correlate with survival after recurrence. Methods We performed a retrospective review of records from 271 patients with recurrent metastatic HR+/HER2- breast cancer diagnosed between January 2000 and December 2015. We assessed survival after recurrence according to the metastatic distribution patterns of the first metastatic sites and identified significant prognostic factors among patients with single and multiple metastases. Results Prognosis was significantly better in patients with a single metastasis than in those with multiple metastases (median overall survival after recurrence: 5.86 years vs. 2.50 years, respectively, p < 0.001). No metastatic organ site with single metastasis was significantly associated with prognostic outcome, although single metastasis with diffuse lesions was an independent risk factor for worse prognosis (HR: 3.641; 95% CI: 1.856–7.141) and more easily progressing to multiple metastases (p = 0.002). Multiple metastases, including liver metastasis (HR: 3.145; 95% CI: 1.802–5.495) or brain metastasis (HR: 3.289; 95% CI: 1.355–7.937), were regarded as significant independent poor prognostic factors; however, multiple metastases not involving liver or brain metastasis were not significantly related to prognosis after recurrence. Conclusions Single metastases with diffuse lesions could more easily disseminate systemically and progress to multiple metastases, leading to a poor prognosis similar to multiple metastases. Our findings indicate that the reconsideration of the determinant factors of therapeutic strategies for first recurrence in HR+/HER2- breast cancer may be needed.

Tumour Evolution and Seed and Soil Mechanism in Pancreatic Metastases of Renal Cell Carcinoma

In metastatic renal cell carcinoma, pancreatic metastases can appear in two clinical manifestations: (a) very rarely as isolated pancreatic metastases and (b) in the context with multi-organ metastatic disease. Both courses are characterised by rare, unusual clinical features. For isolated pancreatic metastases, the literature shows no effect on survival in all 11 publications that examined the effect of singular versus multiple pancreatic metastases; a lack of effect on survival time was also present in all 8 studies on pancreatic metastases size, in 7 of 8 studies on the influence of disease-free interval (DFI), and in 6 of 7 studies on the influence of synchronous versus metachronous metastases. In multi-organ site metastases observations, on the other hand, all five available references showed significantly better results in patients with concurrent pancreatic metastases compared to those without pancreatic metastases, although the total number of affected organs in the pancreatic metastases cohort was larger. Tumour volume-dependent risk factors thus remain surprisingly ineffective in both groups, which contradicts the usual behaviour of solid tumours. The reasons for this unusual behaviour and possible relations to tumour evolution and the hypothesis of an influence of a seed and soil mechanism in the occurrence of pancreatic metastases in metastatic renal cell carcinoma are discussed.

Enhanced communication of IARC Monograph findings to better achieve public health outcomes

IARC Monographs are globally-recognized assessments of carcinogenicity published by International Agency for Research on Cancer and directed to national authorities as a contribution to public health. Currently, though not constraining the scope of studies examined, Monographs are declared to involve only hazard identification: a scenario which then dictates that overall evaluations involve a single sentence referencing only the likelihood of carcinogenicity. Consequently, for notable evaluations, commentators explain what particular Monographs encompass, sometimes indicating which national authority might act. However, upon examination, IARC Monographs cannot be recognized as only hazard identification because they include assessment of specified circumstances of exposure, document levels of exposure to particular agents and identify organ site(s) for tumours. Comparisons with assessments of carcinogenicity made by US National Toxicology Program and by World Cancer Research Fund indicate that Monographs represent a singular methodology, not precisely aligned with hazard identification or risk assessment. Hence, all key findings relevant to public health in particular Monographs may be prominently and accessibly communicated. Where currently documented, these findings specifically include situation(s) resulting in highest exposure and known or likely tumour site(s). Correspondingly-less reliance on commentators, and greater insight by the wider community, may be further achieved by WHO, in consultation with IARC, describing the type of national authority relevant to particular evaluations, this information being complementary to relevant Monographs. No changes in the scope, structure or content of Monographs are necessitated by such proposals. Examples of key findings, and the relevant national authority, are provided in respect of several notable Monographs.

New insights into patterns of first metastatic sites influencing survival of patients with hormone receptor-positive, HER2-negative breast cancer: a multicenter study of 271 patients

Background: The initial therapeutic strategy for hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer is based on the first metastatic site, but little evidence is available regarding the influence of metastatic distribution patterns of first metastatic sites on prognosis. In this study, we aimed to identify the metastatic distribution patterns of first metastatic sites that significantly correlate with survival after recurrence.Methods: We performed a retrospective review of records from 271 patients with recurrent metastatic HR+/ HER2- breast cancer diagnosed between January 2000 and December 2015. We assessed survival after recurrence according to the metastatic distribution patterns of first metastatic sites and identified significant prognostic factors among the patients with single and multiple metastases.Results: Prognosis was significantly better in patients with single metastasis than those with multiple metastases (median overall survival after recurrence: 5.86 years vs. 2.50 years, p<0.001). No metastatic organ site with single metastasis was significantly associated with prognostic outcome, though single metastasis with diffuse lesions was an independent risk factor for worse prognosis (HR: 3.641; 95% CI: 1.856-7.141), and more easily progressed to multiple metastases (p=0.002). Multiple metastases including liver metastasis (HR: 3.145; 95% CI: 1.802-5.495) or brain metastasis (HR: 3.289; 95% CI: 1.355-7.937) were regarded as a significant independent poor prognostic factor, but multiple metastases not involving liver or brain metastasis were not significantly related to prognosis after recurrence.Conclusions: Single metastasis with diffuse lesions could more easily disseminate systemically and progress to multiple metastases, leading to poor prognosis similar to multiple metastases. Our findings indicate that reconsideration of the determinant factors of therapeutic strategies for first recurrence in HR+/HER2- breast cancer may be needed.