Emilie Lanoy

Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination

Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

BACKGROUND Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. OBJECTIVE To identify the optimal CD4 cell count at which cART should be initiated. DESIGN Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L. SETTING HIV clinics in Europe and the Veterans Health Administration system in the United States. PATIENTS 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis. MEASUREMENTS Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. RESULTS Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. LIMITATIONS CD4 cell count at cART initiation was not randomized. Residual confounding may exist. CONCLUSION Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival

BACKGROUND Ipilimumab is a recently approved immunotherapy that has demonstrated an improvement in the overall survival (OS) of patients with metastatic melanoma. We report a single-institution experience in patients treated in a compassionate-use program. PATIENTS AND METHODS In this prospective study, patients were treated between June 2010 and September 2011. Inclusion criteria were a diagnosis of unresectable stage III or IV melanoma, at least one previous line of chemotherapy, and survival 12 weeks after the first perfusion. Four courses of ipilimumab were administered at a dose of 3 mg/kg every 3 weeks. RESULTS Seventy-three patients were included. Median OS was 9.1 months (95% CI 6.4-11.3) from the start of ipilimumab. Immune-related adverse events were observed in 45 patients (62%), including 19 grade 3-4 events (26%). No drug-related death occurred. A lymphocyte count >1000/mm(3) at the start of the second course and an increase in the eosinophil count >100/mm(3) between the first and second infusions were correlated with an improved OS. CONCLUSION Ipilimumab toxic effect is manageable in real life. Biological data such as lymphocyte and eosinophil counts at the time of the second ipilimumab infusion appear to be early markers associated with better OS.

Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab

IMPORTANCE Vitiligo is an autoimmune skin disorder that reacts against melanocytes. The association of vitiligo with tumor response in patients with melanoma who undergo immunotherapy has been reported but is still controversial. OBJECTIVE To prospectively evaluate the appearance of vitiligo in patients receiving pembrolizumab, a monoclonal antibody directed against the programmed death cell receptor. DESIGN, SETTING, AND PARTICIPANTS This prospective observational study was conducted from January 1, 2012, through September 24, 2013, in a single tertiary care hospital with a unit dedicated to patients with melanoma. Sixty-seven patients with metastatic melanoma who received pembrolizumab treatment in the context of a phase 1 study were included and screened for the emergence of vitiligo. Data were collected from January 1, 2012, to February 28, 2014, and analyzed from February through December 2014. MAIN OUTCOMES AND MEASURES Objective tumor response with regard to the occurrence of vitiligo in patients receiving pembrolizumab therapy. Correlation between vitiligo occurrence and overall survival was also estimated using the Kaplan-Meier product-limit method and compared with a log-rank test. To prevent guarantee- or lead-time bias, a landmark analysis approach after 12, 16, and 20 weeks of treatment was retained. RESULTS Of the 67 patients included in the study, 17 (25%) developed vitiligo during pembrolizumab treatment and 50 (75%) did not. An objective (complete or partial) response to treatment was associated with a higher occurrence of vitiligo (12 of 17 [71%] vs 14 of 50 [28%]; P = .002). The time to onset of vitiligo ranged from 52 to 453 (median, 126) days from the start of treatment. Of the 17 patients with vitiligo, 3 (18%) had a complete response, 9 (53%) had a partial response, 3 (18%) had stable disease, and 2 (12%) had progressive disease at the final follow-up. All the patients treated with pembrolizumab who developed vitiligo were alive at the time of analysis, with a median follow-up of 441 days. CONCLUSIONS AND RELEVANCE Vitiligo, a clinically visible immune-related adverse event could be associated with clinical benefit in the context of pembrolizumab treatment.

Skeletal muscle density predicts prognosis in patients with metastatic renal cell carcinoma treated with targeted therapies

Studies have shown that skeletal muscle and adipose tissue are linked to overall survival (OS) and progression‐free survival (PFS). Because targeted therapies have improved the outcome in patients with metastatic renal cell carcinoma (mRCC), new prognostic parameters are required. The objective of the current study was to analyze whether body composition parameters play a prognostic role in patients with mRCC.

Epidemiology of nonkeratinocytic skin cancers among persons with AIDS in the United States.

Objective:Immunosuppression may increase risk for some skin cancers. We evaluated skin cancer epidemiology among persons with AIDS. Design:We linked data from population-based US AIDS and cancer registries to evaluate risk of nonkeratinocytic skin cancers (melanoma, Merkel cell carcinoma, and appendageal carcinomas, including sebaceous carcinoma) in 497 142 persons with AIDS. Methods:Standardized incidence ratios (SIRs) were calculated to relate skin cancer risk to that in the general population. We used logistic regression to compare risk according to demographic factors, CD4 cell count, and a geographic index of ultraviolet radiation exposure. Results:From 60 months before to 60 months after AIDS onset, persons with AIDS had elevated risks of melanoma (SIR = 1.3, 95% confidence interval 1.1–1.4, n = 292 cases) and, more strongly, of Merkel cell carcinoma (SIR = 11, 95% confidence interval 6.3–17, n = 17) and sebaceous carcinoma (SIR = 8.1, 95% confidence interval 3.2–17, n = 7). Risk for appendageal carcinomas increased with progressive time relative to AIDS onset (P trend = 0.03). Risk of these skin cancers was higher in non-Hispanic whites than other racial/ethnic groups, and melanoma risk was highest among men who have sex with men. Melanoma risk was unrelated to CD4 cell count at AIDS onset (P = 0.32). Risks for melanoma and appendageal carcinomas rose with increasing ultraviolet radiation exposure (P trend <10−4 and P trend = 10−3, respectively). Conclusion:Among persons with AIDS, there is a modest excess risk of melanoma, which is not strongly related to immunosuppression and may relate to ultraviolet radiation exposure. In contrast, the greatly increased risks for Merkel cell and sebaceous carcinoma suggest an etiologic role for immunosuppression.

Skin cancers associated with HIV infection and solid-organ transplantation among elderly adults.

Immunosuppression may be etiologic for some skin cancers. We investigated the impact of human immunodeficiency virus (HIV) infection and solid‐organ transplantation on skin cancer risk. We conducted a population‐based case–control study among elderly U.S. adults (non‐Hispanic whites, age 67 years or older), using Surveillance, Epidemiology and End Results Medicare linked data. The study comprised 29,926 skin cancer cases (excluding basal cell and squamous cell carcinomas) and 119,704 controls, frequency‐matched by gender, age and calendar year (1987–2002). Medicare claims identified solid‐organ transplantation or HIV infection before cancer diagnosis/control selection. As negative controls, we evaluated other medical conditions (e.g., hypertension and depression) and cancers (breast, colon and prostate) not linked to immunosuppression. Odds ratios (ORs) compared prevalence in cases and controls, adjusted for matching factors and number of prior physician claims. Risks of Kaposi sarcoma (N = 602) and cutaneous non‐Hodgkin lymphoma (N = 1,836) were increased with solid‐organ transplantation (OR [95%CI]: 11.06 [5.27–23.23] and 2.27 [1.00–5.15], respectively) and HIV infection (21.58 [11.94–38.99] and 2.41 [1.05–5.52], respectively). Solid‐organ transplantation was also associated with increased risks of Merkel cell carcinoma (N = 1,286; OR [95%CI] 4.95 [2.62–9.34]) and other cutaneous sarcomas (N = 972; 4.19 [1.83–9.56]). Solid‐organ transplantation was nonsignificantly associated with melanoma (N = 23,974; (OR 1.36 [95%CI 0.98–1.88]). Null or weak associations were observed for negative control medical conditions and cancers. Solid‐organ transplantation and HIV infection were followed by increased risk for some skin cancer subtypes among elderly adults. These results highlight the potential role of immunity in development of skin cancers.

The spectrum of malignancies in HIV-infected patients in 2006 in France: The ONCOVIH study†‡

Since no large descriptive studies of incident cancers in HIV‐infected patients are available in France, the nationwide cross‐sectional ONCOVIH study aimed to prospectively report new malignancies diagnosed in HIV‐infected patients in cancer centers and HIV/AIDS centers. We estimated the number of cancers in France for the year 2006 using the capture–recapture methods with two sources: ONCOVIH and the FHDH ANRS‐CO4 cohort, as well as the completeness of the sources. Incidence and relative risks (RR) to the general population were estimated. In 2006, 672 new malignancies in 668 patients were reported in ONCOVIH; the most common were non Hodgkins lymphoma (NHL, 21.5%), Kaposis sarcoma (KS, 16.0%), lung cancer (9.4%), anal cancer (8.2%), Hodgkins lymphoma (7.6%), skin cancers excluding melanoma (6.8%), and liver cancer (5.6%). Based on the capture‐recapture approach, the estimated number of malignancies was 1320 and non‐AIDS‐defining malignancies (NADM) represented 68% of cases. The overall ascertainment of malignancies were 53%, and 59%, in the ONCOVIH study, and the FHDH ANRS‐CO4 cohort, respectively. The estimated incidence of cancer among HIV‐infected patients was 14 per 1000 person‐years. Compared with the general population, the estimated RR in HIV–infected patients was 3.5 (95%CI 3.3–3.8) in men and 3.6 (95%CI 3.2–4.0) in women, and was particularly elevated in younger patients. Even in the era of combined antiretroviral therapy, the incidence of cancer is higher in HIV‐infected persons than in the general population. A large variety of malignancies were diagnosed, and the majority were NADM.

Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab

Background Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma (MM) but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity. Patients and methods Twenty-six patients with MM treated with ipilimumab were prospectively enrolled. Fecal microbiota composition was assessed using 16S rRNA gene sequencing at baseline and before each ipilimumab infusion. Patients were further clustered based on microbiota patterns. Peripheral blood lymphocytes immunophenotypes were studied in parallel. Results A distinct baseline gut microbiota composition was associated with both clinical response and colitis. Compared with patients whose baseline microbiota was driven by Bacteroides (cluster B, n = 10), patients whose baseline microbiota was enriched with Faecalibacterium genus and other Firmicutes (cluster A, n = 12) had longer progression-free survival (P = 0.0039) and overall survival (P = 0.051). Most of the baseline colitis-associated phylotypes were related to Firmicutes (e.g. relatives of Faecalibacterium prausnitzii and Gemmiger formicilis), whereas no colitis-related phylotypes were assigned to Bacteroidetes. A low proportion of peripheral blood regulatory T cells was associated with cluster A, long-term clinical benefit and colitis. Ipilimumab led to a higher inducible T-cell COStimulator induction on CD4+ T cells and to a higher increase in serum CD25 in patients who belonged to Faecalibacterium-driven cluster A. Conclusion Baseline gut microbiota enriched with Faecalibacterium and other Firmicutes is associated with beneficial clinical response to ipilimumab and more frequent occurrence of ipilimumab-induced colitis.

Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions

Objective: The link between CNS penetration of antiretrovirals and AIDS-defining neurologic disorders remains largely unknown. Methods: HIV-infected, antiretroviral therapy–naive individuals in the HIV-CAUSAL Collaboration who started an antiretroviral regimen were classified according to the CNS Penetration Effectiveness (CPE) score of their initial regimen into low (<8), medium (8–9), or high (>9) CPE score. We estimated “intention-to-treat” hazard ratios of 4 neuroAIDS conditions for baseline regimens with high and medium CPE scores compared with regimens with a low score. We used inverse probability weighting to adjust for potential bias due to infrequent follow-up. Results: A total of 61,938 individuals were followed for a median (interquartile range) of 37 (18, 70) months. During follow-up, there were 235 cases of HIV dementia, 169 cases of toxoplasmosis, 128 cases of cryptococcal meningitis, and 141 cases of progressive multifocal leukoencephalopathy. The hazard ratio (95% confidence interval) for initiating a combined antiretroviral therapy regimen with a high vs low CPE score was 1.74 (1.15, 2.65) for HIV dementia, 0.90 (0.50, 1.62) for toxoplasmosis, 1.13 (0.61, 2.11) for cryptococcal meningitis, and 1.32 (0.71, 2.47) for progressive multifocal leukoencephalopathy. The respective hazard ratios (95% confidence intervals) for a medium vs low CPE score were 1.01 (0.73, 1.39), 0.80 (0.56, 1.15), 1.08 (0.73, 1.62), and 1.08 (0.73, 1.58). Conclusions: We estimated that initiation of a combined antiretroviral therapy regimen with a high CPE score increases the risk of HIV dementia, but not of other neuroAIDS conditions.