Immunotherapy in Melanoma: Highlights for the General Practitioner.

Melanoma is the most aggressive skin cancer, and surgery is the standard of care for localised disease. However, a risk of local and distant relapse exists despite tumour removal, particularly with thick or ulcerated tumours or lymph node involvement. Immunotherapy with immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L-1 or CTLA-4 demonstrated improved relapse-free survival and distant metastasis-free survival against placebo after surgery for stage-III and high-risk stage-II melanoma. In unresectable localised and metastatic tumours, the double immunotherapy with ICIs (anti-PD-1+ anti-CTLA-4) allows for long-term survival in more than 50% of the patients. Novel immunotherapies (anti-LAG-3 ICI, adoptive cell therapy, intra-tumoural immunotherapy, cancer vaccines) and new combinations are in development to overcome resistance and improve patients' survival. Therapeutic decisions for each patient should be discussed in a specialised multidisciplinary team.

Cardiovascular, Renal and Pulmonary Toxicity of Immune Checkpoint Inhibitors in Cancer: What the GP Should Know.

Immunotherapy with immune checkpoint inhibitors (ICI) is administered in different cancer types and can lead to a wide range of immune-related adverse events including toxicity in vital organs such as the lungs, the kidneys, and the heart. The main hypothesis suggests an overactivation of the immune cells in the different organs. Whereas immune-related cardiotoxicity is very rare but life threatening, ICI-induced acute kidney injury and pneumonitis are more frequent but in general less severe. Renal toxicity corresponds in more than 90% to an acute tubulo-interstitial nephritis. Checkpoint inhibitors pneumonitis is diagnosed mainly on respiratory symptoms with new radiological features, especially under the form of a cryptogenic organising pneumonia. Cardiotoxicity is predominantly marked by myocarditis but also pericarditis and arrhythmias, among others. Early recognition, temporary or definitive cessation of ICI therapy and rapid initiation of high-dose corticosteroids are the cornerstones of the management, which must to be multidisciplinary in a specialised center.

[CAR-T Cells in solid tumours: present and future]. / Cellules CAR-T pour le traitement des tumeurs solides : présent et futur.

Adoptive cell therapy with CAR-T cells (Chimeric Antigen Receptor T-cells) genetically modifies T lymphocytes in such a way that they express a new receptor capable of targeting certain specific tumor antigens. This therapy showed impressive results in some hematological malignancies but still faces many hurdles in the treatment of solid tumours. Indeed, paucity of antigen targets, antigen heterogeneity, poor trafficking to the tumor site and the immunosuppressive tumour microenvironment are the main challenges in solid tumours. The rapid advancement of CARs technologies, coupled with a better understanding of the mechanisms of efficiency, toxicity and resistance, pave the way for the success of CAR-T cells in solid tumours.

La thérapie cellulaire adoptive par cellules CAR-T (CAR-T cells, Chimeric Antigen Receptor T-cells) permet de modifier génétiquement des lymphocytes T de telle sorte qu'ils expriment un nouveau récepteur capable de cibler des antigènes tumoraux spécifiques. Cette thérapie montre des résultats impressionnants dans certaines hémopathies malignes mais rencontre encore de nombreux obstacles dans le traitement des tumeurs solides. En effet, la paucité des cibles antigéniques, l'hétérogénéité antigénique, la difficulté d'accès au site tumoral et le microenvironnement tumoral immunosuppressif constituent les principaux défis à surmonter dans les tumeurs solides. L'avancement rapide des technologies CAR couplé à une meilleure compréhension des mécanismes d'efficacité, toxicité et résistance tracent le chemin du succès des cellules CAR-T dans les tumeurs solides.

The T cell differentiation landscape is shaped by tumour mutations in lung cancer.

Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.

Publisher Correction: Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.

Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.

Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment.

Despite the advances in cancer immunotherapy, only a fraction of patients with bladder cancer exhibit responses to checkpoint blockade, highlighting a need to better understand drug resistance and identify rational immunotherapy combinations. However, accessibility to the tumor prior and during therapy is a major limitation in understanding the immune tumor microenvironment (TME). Herein, we identified urine-derived lymphocytes (UDLs) as a readily accessible source of T cells in 32 patients with muscle invasive bladder cancer (MIBC). We observed that effector CD8+ and CD4+ cells and regulatory T cells within the urine accurately map the immune checkpoint landscape and T cell receptor repertoire of the TME. Finally, an increased UDL count, specifically high expression of PD-1 (PD-1hi) on CD8+ at the time of cystectomy, was associated with a shorter recurrence-free survival. UDL analysis represents a dynamic liquid biopsy that is representative of the bladder immune TME that may be used to identify actionable immuno-oncology (IO) targets with potential prognostic value in MIBC.

Expansion of airway basal epithelial cells from primary human non-small cell lung cancer tumors.

Pre-clinical non-small cell lung cancer (NSCLC) models are poorly representative of the considerable inter- and intra-tumor heterogeneity of the disease in patients. Primary cell-based in vitro models of NSCLC are therefore desirable for novel therapy development and personalized cancer medicine. Methods have been described to generate rapidly proliferating epithelial cell cultures from multiple human epithelia using 3T3-J2 feeder cell culture in the presence of Y-27632, a RHO-associated protein kinase (ROCK) inhibitor, in what are known as "conditional reprograming conditions" (CRC) or 3T3 + Y. In some cancer studies, variations of this methodology have allowed primary tumor cell expansion across a number of cancer types but other studies have demonstrated the preferential expansion of normal epithelial cells from tumors in such conditions. Here, we report our experience regarding the derivation of primary NSCLC cell cultures from 12 lung adenocarcinoma patients enrolled in the Tracking Cancer Evolution through Therapy (TRACERx) clinical study and discuss these in the context of improving the success rate for in vitro cultivation of cells from NSCLC tumors.

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.

[Vademecum of skeletal complications of malignancy]. / Vademecum des complications osseuses des cancers.

Bone metastasis is a frequent complication for cancer patients leading pain, fracture, spinal cord compression and hypercalcemia. A multidisciplinary approach is strongly recommended to optimize the different treatment options (i.e. radiotherapy, surgery and vertebroplasty) in the context of the underlying cancer. The effectiveness of bisphosphonates and denosumab to reduce skeletal events has widely been demonstrated. Prevention and treatment of bone complications are crucial for maintaining the independence and quality of life of patients.

[HPV-related cancer: should young men be vaccinated?]. / Cancers liés au HPV: faut-il vacciner les jeunes hommes?

HPV infection, a sexually transmissible disease, causes squamous cell carcinoma in a small fraction of infected individuals, years after exposure. Several cancers both in female and male, such as cervical cancer, anal carcinoma and up to 50% of oropharyngeal tumors are related to serotypes 16 and 18 of HPV. Several studies evaluating vaccination of young women before HPV exposure showed very good protection against cervical dysplasia and carcinoma in situ. Health authorities' guidelines now widely recommend vaccination of female between 11 and 14 years old. Results of recent trials also reveal good protective effect in men, raising the question of immunizing both young women and men. Important medical and socio-economic issues will need to be addressed before implementing such program.

[Is lung cancer in women different?]. / Le cancer du poumon chez la femme est-il différent?

Lung cancer is the leading cause of cancer death in the world, favored by smoking. Nonsmall cell lung cancer is a heterogeneous disease whose prevalence is increasing among women. Epidemiological, hormonal and pathological factors explain tumor differences between men and women. Women have more frequently adenocarcinomas, EGFR mutations and respond better to cancer treatments. In recent decades, many advances have been made, allowing us to move from histological to molecular characterization of lung tumors. Further analysis of gender disparities will help us to understand and improve the management of patients with NSCLC.