Immuno-oncology-101: overview of major concepts and translational perspectives.

Cancer immunotherapy is demonstrating impressive clinical benefit in different malignancies and clinical oncologists are increasingly turning their attention to immune-oncology. It is now well recognized that innate and adaptive immune cells infiltrating tumors are associated with clinical outcomes and responses to treatments, and can be harnessed to patients' benefit. Considerable advances have also been made in understanding how cancers escape from immune attack. Targeting of immunological escape processes regulated by the expression of immune checkpoint receptors and ligands and the down-modulation of tumor antigen presentation is the basis of immuno-oncology treatments. Despite recent achievements, there remain a number of unresolved issues in order to successfully implement cancer immunotherapy in many cancers. Importantly, clinical biomarkers are still needed for better optimization of emerging combination immunotherapies and better treatment tailoring. In this review, we summarize the function of innate and adaptive immune cells in anti-tumor immunity and the general mechanisms exploited by tumor cells to escape and inhibit immune responses as well as therapeutic strategies developed to overcome these mechanisms and discuss emerging biomarkers in immuno-oncology.

The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?

Immune-checkpoint inhibitors (ICI) now represent the standard of care for several cancer types. In pre-clinical models, absence of an intact gut microbiome negatively impacted ICI efficacy and these findings permitted to unravel the importance of the commensal microbiota in immuno-oncology. Recently, multiple clinical studies including more than 1800 patients in aggregate demonstrated the negative predictive impact of treatments with broad-spectrum antibiotics (ATB) on cancer patients receiving ICI. Altogether, these results have led to the hypothesis that ATB-induced dysbiosis might influence the clinical response through the modulation of the gut microbiome. Controversy still remains, as ATB treatment might simply constitute a surrogate marker of unfit or immunodeficient patients. In this review, we summarize recent publications addressing the impact of the gut microbiome on ICI efficacy, discuss currently available data on the effect of ATB administered in different time-frames respect to ICI initiation, and finally, evoke the therapeutic implications of these findings.

T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for MHC class I loss variants.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancer (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy. PATIENTS AND METHODS: We analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes [metastatic lymph nodes (mLN)] in early BC (EBC) after exposure to T-cell bispecific antibodies (TCB) bridging CD3ε and human epidermal growth factor receptor 2 (HER2) or Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5), before and after chemotherapy. Human leukocyte antigen (HLA) class I loss was assessed by whole exome sequencing and immunohistochemistry. One hundred primary BC, 64 surrounding 'healthy tissue' and 24 mLN-related parameters were analyzed. RESULTS: HLA loss of heterozygosity was observed in EBC, at a clonal and subclonal level and was associated with regulatory T cells and T-cell immunoglobulin and mucin-domain-3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3ε and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN. CONCLUSION: TCB should be developed in BC to circumvent low MHC/peptide complexes.

Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer.

Background: The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI. Patients and methods: We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed. Results: Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were ß-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4-6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0-2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6-7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC. Conclusion: ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.

Imatinib for highly chemoresistant Kaposi sarcoma in a patient with long-term HIV control: a case report and literature review.

Kaposi sarcoma (ks) is a vascular tumour caused by oncogenic human herpesvirus type 8; it often occurs with hiv-associated immunosuppression. Numerous cellular signalling pathways are involved in the pathogenesis of ks, among which receptor tyrosine kinases such as the c-Kit and platelet-derived growth factor receptors play an important role. Imatinib mesylate, a tyrosine kinase inhibitor, has resulted in partial regression of ks lesions in one third of treated patients, but its mechanism of action remains unclear. Here, we report the case of a white man with recurrent ks despite well-suppressed hiv infection and multiple chemotherapies who received imatinib and showed a complete and sustained tumour response. To our knowledge, this report is the first showing the value of imatinib in the management of ks in the context of long-lasting hiv control with adequate quantitative CD4 recovery. Our case indicates that imatinib can be a treatment option for highly chemoresistant recurrent ks in patients on long-term antiretroviral therapy.

Therapeutic landscape of metastatic non-small-cell lung cancer in Canada in 2020.

Lung cancer is the most commonly diagnosed cancer in Canada and remains associated with high mortality. Nevertheless, recent advances in the fields of immuno-oncology and precision medicine have led to significant improvements in clinical outcome in metastatic non-small-cell lung cancer (nsclc). Those improvements were facilitated by a greater understanding of the biologic classification of nsclc, which catalyzed discoveries of novel therapies. Here, we present a comprehensive review of the recent avalanche of practice-changing trials in metastatic nsclc, and we offer an approach to the management of this disease from a Canadian perspective. We begin with an overview of the pathologic and molecular characterization of metastatic nsclc. Next, we review the indications for currently approved immune checkpoint inhibitors, and we provide an approach to the management of disease with a driver mutation. Finally, we address future avenues in both diagnostics and therapeutics for patients with advanced and metastatic nsclc.

Erratum: Therapeutic landscape of metastatic non-small-cell lung cancer in Canada in 2020.

[This corrects the article DOI: 10.3747/co.27.5953.].

Multiple remissions of extracavitary primary effusion lymphoma treated with a single cycle of liposomal doxorubicin in a patient infected with HIV.

Primary effusion lymphoma (pel) is a rare human herpesvirus 8 (hhv8)-related large B cell lymphoma with plasmablastic, immunoblastic, or anaplastic features that often carries a poor prognosis. This lymphoma occurs mainly in patients with hiv infection, most often with Epstein-Barr virus (ebv) co-infection, and usually presents as body cavity effusions or, less commonly, as extracavitary lesions without effusion (ec-pel). Chemotherapeutic treatment options are limited and require concurrent antiretroviral therapy (art). Here, we report the case of an adult patient with hiv infection and chronic hepatitis E virus (hev) co-infection who had low CD4 T cell recovery after years of art. The patient then developed a cutaneous ec-pel which rapidly regressed after 1 cycle of liposomal doxorubicin (ld) for his Kaposi sarcoma (ks) before treatment with chop chemotherapy. He had previously received numerous cycles of ld for cutaneous ks over 2 years. Because of the patient's low CD4 T cell count, hev co-infection, and earlier unexpected remission of ec-pel before chop, the patient opted for a single trial of ld before other options. Surprisingly, he experienced a complete remission lasting 18 months. Subsequently, his ec-pel relapsed twice at 31 and at 41 months after the initial diagnosis. Upon recurrence, a similar single cycle of ld was given, which again induced remission. The patient today is in complete remission after a total of 4 ld infusions over 54 months. This patient represents a unique case of hiv-with-hhv8-related, ebv-negative ec-pel with chronic hev coinfection, in which rapid remission was achieved after a single cycle of ld, suggesting an antiviral response in addition to the chemotherapeutic effect.

Pulmonary Langerhans Cell Histiocytosis with Lytic Bone Involvement in an Adult Smoker: Regression following Smoking Cessation.

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the proliferation and dissemination of histiocytes. These in turn may cause symptoms ranging from isolated, infiltrative lesions to severe multisystem disease. Pulmonary Langerhans cell histiocytosis (PLCH) presents as a localized polyclonal proliferation of Langerhans cells in the lungs causing bilateral cysts and fibrosis. In adults, this rare condition is considered a reactive process associated with cigarette smoking. Recently, clonal proliferation has been reported with the presence of BRAF V600E oncogenic mutation in a subset of PLCH patients. Spontaneous resolution was described; however, based on case series, smoking cessation remains the most effective way to achieve complete remission and prevent long term complications related to tobacco. Herein, we report the case of an adult woman with biopsy-proven PLCH presenting with thoracic (T8) vertebral bone destruction. Both the lung and the bone diseases regressed following smoking cessation, representing a rare case of synchronous disseminated PCLH with bone localization. This observation underscores the contribution of cigarette smoking as a systemic trigger of both pulmonary and extrapulmonary bone lesions. A review of similar cases in the literature is also presented.

Vascular endothelial cell function in catastrophic antiphospholipid syndrome: a case report and review of the literature.

Catastrophic antiphospholipid syndrome (CAPS) is a rare autoimmune condition, which has been associated with a high mortality rate. However, with current management that includes a combination of anticoagulation, glucocorticoid administration, and plasma exchange, mortality rate has declined. Despite survival improvement with new generation immunosuppressive agents, their mechanisms of action are poorly defined, and CAPS is still considered a high-risk complication in patients known with antiphospholipid antibody syndrome. Herein, we present a case of a 79-year-old male who presented with a myocardial infarct and renal failure secondary to CAPS following a splenectomy for immune thrombocytopenia. Regardless of rapid combination of first-line treatment and rituximab therapy, the patient developed lethal cardiogenic shock secondary to mitral valve papillary muscle necrosis. Discussion of the pathophysiology and avenues of future therapies in CAPS are reported.