Targeting Resident Memory T Cells for Cancer Immunotherapy

A novel population of memory CD8+ T cells called resident memory T cells (TRM) has been identified based on their phenotype (CD103, CD69) and on their local tissue residency without recirculating in the blood. These cells have been implicated in protective immune response against pathogens in both animal models and humans. Their role in cancer is just emerging as a key player in tumor immunosurveillance. Many properties of these cells suggest that they could control tumor growth: (i) they respond much faster to reexposure to cognate antigen than circulating memory cells, (ii) they express high levels of cytotoxic molecules, and (iii) they are enriched in tumor-specific T cells in close contact with tumor cells. TRM are present in many human cancers and are associated with a good clinical outcome independently of the infiltration of CD8+ T cells. It has been recently shown that the efficacy of cancer vaccines depends on their ability to elicit TRM. In adoptive cell therapy, the transfer of cells with the ability to establish TRM at the tumor site correlates with the potency of this approach. Interestingly, TRM express immune checkpoint molecules and preliminary data showed that they could expand early during anti-PD-1 treatment, and thus be considered as a surrogate marker of response to immunotherapy. Some cues to better expand these cells in vivo and improve the success of cancer immunotherapy include using mucosal routes of immunization, targeting subpopulations of dendritic cells as well as local signal at the mucosal site to recruit them in mucosal tissue

Is There Still Room for Cancer Vaccines at the Era of Checkpoint Inhibitors

Checkpoint inhibitor (CPI) blockade is considered to be a revolution in cancer therapy, although most patients (70%–80%) remain resistant to this therapy. It has been hypothesized that only tumors with high mutation rates generate a natural antitumor T cell response, which could be revigorated by this therapy. In patients with no pre-existing antitumor T cells, a vaccine-induced T cell response is a rational option to counteract clinical resistance. This hypothesis has been validated in preclinical models using various cancer vaccines combined with inhibitory pathway blockade (PD-1-PDL1-2, CTLA-4-CD80-CD86). Enhanced T cell infiltration of various tumors has been demonstrated following this combination therapy. The timing of this combination appears to be critical to the success of this therapy and multiple combinations of immunomodulating antibodies (CPI antagonists or costimulatory pathway agonists) have reinforced the synergy with cancer vaccines. Only limited results are available in humans and this combined approach has yet to be validated. Comprehensive monitoring of the regulation of CPI and costimulatory molecules after administration of immunomodulatory antibodies (anti-PD1/PD-L1, anti-CTLA-4, anti-OX40, etc.) and cancer vaccines should help to guide the selection of the best combination and timing of this therapy

Prognostic Value of Baseline Neutrophil-to-Lymphocyte Ratio in Metastatic Urothelial Carcinoma Patients Treated With First-line Chemotherapy: A Large Multicenter Study

This multicenter study assessed the prognostic value of the neutrophile-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation, for overall survival (OS) and progression-free survival (PFS) after first-line chemotherapy (CT) in 280 metastatic urothelial cancer patients. High pre-CT NLR was an independent predictor of reduced of OS (hazard ratio=1.36; P<.0001), highlighting the importance of an inflammatory cancer-related microenvironment

Impact of Patient- and Clinician-Reported Cumulative Toxicity on Quality of Life in Patients With Metastatic Castration-Naive Prostate Cancer

International audienceBackground: Current toxicity evaluation is primarily focused on high-grade adverse events (AEs) reported by clinicians. However, the cumulative effect of multiple lower-grade AEs may also impact patients' quality of life (QoL). Further, patient-reported toxicity may be more representative of patients' treatment experiences. This study aimed to determine whether cumulative toxicity comprising all-grade AEs is more associated with QoL than cumulative toxicity comprising high-grade AEs only, and whether patient-reported cumulative toxicity is more associated with QoL than clinician-reported cumulative toxicity. Methods: Patients with metastatic castration-naive prostate cancer participating in the phase III GETUG-AFU 15 trial completed questionnaires on AEs (at 3 and 6 months) and QoL (at baseline and 3 and 6 months). Clinicians reported AEs during clinical visits. Cumulative toxicity scores were calculated for clinicians and patients in 3 ways: total number of high-grade AEs, total number of all-grade AEs, and total number of all AEs multiplied by their grade (severity score). Relationships between cumulative toxicity scores and QoL were studied using longitudinal regression analyses; unstandardized (B) and standardized regression coefficients (beta) are reported. Results: Of 385 patients, 184 with complete QoL and toxicity data were included. Clinician-reported all-grade AEs (B, -2.2; 95% CI, -3.3 to -1.1; P<.01) and severity score (B, -1.4; 95% CI, -2.2 to -0.7; P<.01) were associated with deteriorated physical QoL, whereas the total number of high-grade AEs was not. All patient-reported scores were significantly (P<.01 for all) associated with deteriorated physical and global QoL. Standardized regression coefficients indicated that patient-reported toxicity scores were more associated with QoL outcomes than clinician-reported scores, with the strongest association found for the all-grade AEs and severity cumulative toxicity scores. Conclusions: Patient-and clinician-based cumulative toxicity scores comprising all-grade AEs better reflect impact on patient QoL than toxicity scores comprising high-grade AEs only. To assess the effect of toxicity on QoL, patient-reported cumulative toxicity scores are preferred

Burden of Metastatic Castrate Naive Prostate Cancer Patients, to Identify Men More Likely to Benefit from Early Docetaxel: Further Analyses of CHAARTED and GETUG-AFU15 Studies

International audienceBACKGROUND:Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D.OBJECTIVE:To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT]).DESIGN, SETTING, AND PARTICIPANTS:Data were accessed from two independent phase III trials of ADT alone or ADT+D-GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The primary end point was OS.RESULTS AND LIMITATIONS:Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p<0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT+D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials.CONCLUSIONS:There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients.PATIENT SUMMARY:Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits

Molecular subtypes of clear cell renal cell carcinoma are associated to sunitinib response in the metastatic setting

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