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

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

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

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Developing strategies for expansion and evaluation of the activity of Neoantigen Reactive T cells in non small cell lung cancer

The advent of immunotherapy with checkpoint inhibitors constitutes a paradigm shift in the oncological therapeutic armamentarium in several solid tumours including NSCLC, with improved response rates and survival. However, despite better outcomes, most of the patients will have disease progression. Therefore, alternate treatment options are needed. Adoptive cell therapy with the transfer of ex vivo expanded autologous T cells showed promising results mainly in melanoma including in heavily pre-treated PD-1 resistant patients. Lung cancer is the leading cause of cancer-related deaths in men and women worldwide and is mainly related to cigarette smoking. NSCLC is characterised by a high tumour mutational burden (TMB) and high tumour infiltrating lymphocytes (TILs) but these cells are often dysfunctional due to chronic antigen exposure within the tumour microenvironment. Our work aimed to analyse the impact of immunomodulation on different checkpoint receptors (4-1BB, ICOS, PD-L1) on TILs number, phenotype, differentiation and TCR repertoire during the ex vivo co-culture of TILs and tumours cells in early stage NSCLC. Activation of 4-1BB or ICOS axis, blocking of PD-L1 pathway and combination of 4-1BB activation and PD-L1 inhibition were tested and revealed that co-stimulation of 4-1BB leads to the highest expansion of differentiated effector memory CD8+ T cells harboring features of exhaustion. In addition, upon 4-1BB activation alone or associated with PD-L1 inhibition, preliminary results of TCR sequencing suggested an increase of ubiquitous TCRs (present in every tumour regions) that may be tumour reactive. Generated PDXs and synthetised neoantigens allowed us to investigate TILs for tumour reactivity. We demonstrated the presence of neoantigen reactive T cells within the expanded T cells and 4-1BB co-stimulation allowed a more potent anti-tumour response compared to the absence of 4-1BB activation. In conclusion, TILs expansion was successful in early stage NSCLC and co-stimulation of 4-1BB enhanced CD8+ T cells proliferation and ubiquitous TCRs and might preferentially increase tumour reactive T cells

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.L’infection à HPV, sexuellement transmissible, confère un risque faible de développer un carcinome épidermoïde après des années de latence. Les cancers liés aux sérotypes 16 et 18 du virus HPV sont nombreux tant chez la femme que chez l’homme, dont le cancer du col de l’utérus, du canal anal et près de 50% des tumeurs de l’oropharynx. Le cancer du col de l’utérus est la seconde cause de décès par cancer chez la femme. La vaccination des jeunes femmes avant l’exposition au HPV induit une très bonne protection contre les précancéroses cervicales. Les recommandations actuelles sont de vacciner les jeunes femmes entre onze et quatorze ans. Les résultats d’études récentes montrent que le vaccin HPV est également efficace chez l’homme. L’intérêt d’une immunisation des jeunes hommes est discuté. Les enjeux médicaux et socio-économiques d’une vaccination des jeunes des deux sexes seront déterminants pour l’implémentation d’un tel programme

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.Le cancer pulmonaire est la première cause de mortalité par cancer dans le monde, favorisée par le tabagisme. Le carcinome pulmonaire non à petites cellules est une maladie hétérogène dont la prévalence augmente chez les femmes. Des facteurs épidémiologiques, pathologiques et hormonaux expliquent les différences tumorales entre hommes et femmes. Ces dernières présentent plus fréquemment des adénocarcinomes, une mutation du gène EGFR (Epidermal growth factor receptor) et répondent mieux aux traitements oncologiques. Ces dernières décennies, de nombreuses avancées ont été réalisées, permettant de passer d’une caractérisation histologique à une caractérisation moléculaire des tumeurs pulmonaires. Une prise en considération des disparités entre genres permettra de mieux comprendre et d’améliorer la prise en charge des patients atteints d’un NSCLC (non-small cell lung cancer)

Cellules CAR-T pour le traitement des tumeurs solides : présent et futur

La thérapie cellulaire adoptive par cellules CAR-T (CAR-T cells, Chimeric Antigen Receptor T-cells) permet de modifier génétique-ment 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

Anticancéreux sous haute tension

Angiogenesis inhibitor drugs, targeting VEGF (vascular endothelial growth factor) are used increasingly in oncology for a wide range of advanced cancers (colorectal cancer, lung cancer, renal cell cancer,...). Generally, they are well tolerated but cardiovascular and renal side effects may appear. The most frequent complications are hypertension and proteinuria which, very often, remain asymptomatic. Therefore, they have to be searched for systematically before and during the treatment. Sometimes, anti-hypertensive medication is needed. We are just beginning to understand the pathophysiological mechanisms of antiangiogenic therapies. Only a multidisciplinary approach will improve our knowledge of those target agents and allow a better management of the cancer patient