Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040.

BACKGROUND: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.

Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040.

BACKGROUND: Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here. PATIENTS AND METHODS: Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion). RESULTS: Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% [95% confidence interval (CI) 12% to 30%] and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. CONCLUSION: With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.

AEDV Expert Consensus Document on the Organization of a Multidisciplinary Unit for Patients With or at Risk of Venereal Infections. / Documento de expertos de la Academia Española de Dermatología y Venereología sobre la organización de una unidad multidisciplinar de atención a pacientes con o en riesgo de infecciones venéreas.

Over the past few years, venereal or sexually transmitted infections (STIs) have been on the rise worldwide requiring additional specialized monographic consultations to specifically treat STIs. Therefore, the Spanish Academy of Dermatology and Venereology (AEDV) Research Working Group on STIs and HIV has drafted this document with the necessary requirements in terms of infrastructure, personnel, technology, specific materials for sample collection, and needs for current therapeutic options. Strict emphasis is placed on the protection of patient privacy. A health care circuit model is outlined too. Additionally, a section has been included on contact tracking and reporting, key elements for the effective prevention and control of STIs. These clinical practice guidelines seek to establish a clinical action framework adapted to the current challenges posed by STIs and HIV in the dermatology, venereology, and multidisciplinary settings.

Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.

Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients.

Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRß sequencing. Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-ß and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1ß concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy.

Dendritic cells (DCs) are the main professional antigen-presenting cells for induction of T-cell adaptive responses. Cancer cells express tumor antigens, including neoantigens generated by nonsynonymous mutations, but are poor for antigen presentation and for providing costimulatory signals for T-cell priming. Mounting evidence suggests that antigen transfer to DCs and their surrogate presentation on major histocompatibility complex class I and II molecules together with costimulatory signals is paramount for induction of viral and cancer immunity. Of the great diversity of DCs, BATF3/IRF8-dependent conventional DCs type 1 (cDC1) excel at cross-presentation of tumor cell-associated antigens. Location of cDC1s in the tumor correlates with improved infiltration by CD8+ T cells and tumor-specific T-cell immunity. Indeed, cDC1s are crucial for antitumor efficacy using checkpoint inhibitors and anti-CD137 agonist monoclonal antibodies in mouse models. Enhancement and exploitation of T-cell cross-priming by cDC1s offer opportunities for improved cancer immunotherapy, including in vivo targeting of tumor antigens to internalizing receptors on cDC1s and strategies to increase their numbers, activation and priming capacity within tumors and tumor-draining lymph nodes.

Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients.

BACKGROUND: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. RESULTS: Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P =  0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P =  0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P =  0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P =  0.001) and NSCLC (P =  0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression. CONCLUSIONS: Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.

Defining the optimal murine models to investigate immune checkpoint blockers and their combination with other immunotherapies.

The recent success of checkpoint blockers to treat cancer has demonstrated that the immune system is a critical player in the war against cancer. Historically, anticancer therapeutics have been tested in syngeneic mouse models (with a fully murine immune system) or in immunodeficient mice that allow the engraftment of human xenografts. Animal models with functioning human immune systems are critically needed to more accurately recapitulate the complexity of the human tumor microenvironment. Such models are integral to better predict tumor responses to both immunomodulatory agents and directly antineoplastic therapies. In this regard, the development of humanized models is a promising, novel strategy that offers the possibility of testing checkpoint blockers' capacity and their combination with other antitumor drugs. In this review, we discuss the strengths and weaknesses of the available animal models regarding their capacity to evaluate checkpoint blockers and checkpoint blocker-based combination immunotherapy.

Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression.

Helper-dependent adenoviral (HDA) vectors constitute excellent gene therapy tools for metabolic liver diseases. We have previously shown that an HDA vector encoding human porphobilinogen deaminase (PBGD) corrects acute intermittent porphyria mice. Now, six non-human primates were injected in the left hepatic lobe with the PBGD-encoding HDA vector to study levels and persistence of transgene expression. Intrahepatic administration of 5 × 10(12) viral particles kg(-1) (10(10) infective units kg(-1)) of HDA only resulted in transient (≈14 weeks) transgene expression in one out of three individuals. In contrast, a more prolonged 90-day immunosuppressive regimen (tacrolimus, mycophenolate, rituximab and steroids) extended meaningful transgene expression for over 76 weeks in two out of two cases. Transgene expression under immunosuppression (IS) reached maximum levels 6 weeks after HDA administration and gradually declined reaching a stable plateau within the therapeutic range for acute porphyria. The non-injected liver lobes also expressed the transgene because of vector circulation. IS controlled anticapsid T-cell responses and decreased the induction of neutralizing antibodies. Re-administration of HDA-hPBGD at week +78 achieved therapeutically meaningful transgene expression only in those animals receiving IS again at the time of this second vector exposure. Overall, immunity against adenoviral capsids poses serious hurdles for long-term HDA-mediated liver transduction, which can be partially circumvented by pharmacological IS.

[Translated article] Descriptive study of spinal instrumentation-related infections in a tertiary hospital.

INTRODUCTION: Spinal instrumentation-related infections (SIRI) are one of the main causes of post-surgical complication and comorbidity. Our objective was to describe the clinical and microbiological characteristics, treatment and prognosis of these infections. MATERIAL AND METHODS: We conducted a retrospective study in our institution (2011-2018) including adult patients undergoing spinal instrumentation who met the diagnostic criteria for confirmed infection. Superficial surgical wound and deep intraoperative samples were processed for microbiological culture. The medical and orthopaedic team was always the same. RESULTS: Forty-one cases were diagnosed of which 39 patients (95.1%) presented early infection (<3 months after initial surgery) with symptoms in the first two weeks, mean CRP at diagnosis was 133mg/dl and 23% associated bacteremia. The remaining two patients (4.8%) were chronic infections (symptoms >3 months after surgery). The treatment of choice in early infections was the Debridement, Antibiotics and Implant Retention (DAIR) strategy without removal of the bone graft, which successfully resolved 84.2% of the infections. The main aetiology was gram-positive (Staphylococcus aureus: 31.7%), followed by gram-negative and polymicrobial flora. Antibiotics were optimised according to cultures with a mean duration of 12 weeks. CONCLUSIONS: In early infections, early diagnosis and DAIR strategy (with bone graft retention) demonstrated a healing rate higher than 80%.

Descriptive study of spinal instrumentation-related infections in a tertiary hospital. / Estudio descriptivo de las infecciones asociadas con instrumentación de columna en un hospital terciario.

INTRODUCTION: Spinal instrumentation-related infections (SIRI) are one of the main causes of post-surgical complication and comorbidity. Our objective was to describe the clinical and microbiological characteristics, treatment and prognosis of these infections. MATERIAL AND METHODS: We conducted a retrospective study in our institution (2011-2018) including adult patients undergoing spinal instrumentation who met the diagnostic criteria for confirmed infection. Superficial surgical wound and deep intraoperative samples were processed for microbiological culture. The medical and orthopaedic team was always the same. RESULTS: Forty-one cases were diagnosed of which 39 patients (95.1%) presented early infection (<3 months after initial surgery) with symptoms in the first two weeks, mean CRP at diagnosis was 133mg/dl and 23% associated bacteremia. The remaining two patients (4.8%) were chronic infections (symptoms >3 months after surgery). The treatment of choice in early infections was the Debridement, Antibiotics and Implant Retention (DAIR) strategy without removal of the bone graft, which successfully resolved 84.2% of the infections. The main etiology was gram-positive (Staphylococcus aureus: 31.7%), followed by gram-negative and polymicrobial flora. Antibiotics were optimized according to cultures with a mean duration of 12 weeks. CONCLUSIONS: In early infections, early diagnosis and DAIR strategy (with bone graft retention) demonstrated a healing rate higher than 80%.

Epidemiology and prevalence of mutations associated with resistance to macrolides and fluoroquinolones in Mycoplasma genitalium in a tertiary hospital from Madrid, Spain.

OBJECTIVE: Mycoplasma genitalium causes persistent sexually transmitted infections. The aims of this study were to estimate the prevalence of resistances to macrolides and fluoroquinolones in M. genitalium and the sexually transmitted coinfections in patients at Hospital Universitario La Paz (Madrid, Spain). METHODS: Patients attended between January and October 2021 were studied. Screening for sexually transmitted pathogens and detection of 23S rRNA and parC genes mutations were performed by real-time PCR (Allplex,SeegeneTM). RESULTS: A total of 1,518 females and 1,136 males were studied. The prevalence of M. genitalium was 2.1%. The macrolides resistance rate was 51.8%. The mutations found were A2059G, A2058T and A2058G. The rate of resistance to fluoroquinolones was 17.8% being the G248T mutation (S83I) the most frequent. Seven males had some sexual transmitted coinfection. CONCLUSIONS: Although the percentage of M. genitalium infections is low, the high rate of resistance to macrolides makes it necessary to revise the protocols for diagnosis and empirical treatment of sexually transmitted infections. The use of fluoroquinolones is appropriate after screening of macrolide resistance profile.

Prevalence of mutations associated with macrolide and fluoroquinolone resistance in Neisseria gonorrhoeae with Allplex NG-DR Assay (Seegene) in a tertiary hospital from Madrid, Spain.

OBJECTIVE: The prevalence of drug-resistant Neisseria gonorrhoeae (NG) infections is increasing. Studies report the prevalence of NG strains presenting A2059G/C2611T (rRNA23S) and S91F (parC) mutations conferring resistance to azithromycin and ciprofloxacin. METHODS: We conducted a prospective cohort study evaluating first void-urine urines, rectal, and oropharyngeal swabs collected from a cohort of patients in a tertiary hospital in Madrid between October 2022 and January 2023. Samples were screened by Allplex 7-STI Essential Assay (Seegene). Drug resistances were performed by Allplex NG-DR Assay (Seegene). RESULTS: A total of 1,415 patients were included, of which 112 had a positive sample for NG infection. One patient had a C2611T mutation (0.9%) and neither patient showed A2059G mutation. We found 67 (59.8%) S91F-positive patients. Forty-four patients (39.3%) not had any mutations. CONCLUSIONS: We report a low-prevalence of mutations A2059G/C2611T to macrolides and a high-prevalence to S91F in NG infections. Molecular methods for the detection of NG resistance could be useful in direct non-culturable samples.

Evaluation of matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry for identification of Candida parapsilosis, C. orthopsilosis and C. metapsilosis.

We have evaluated matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry for the rapid identification of Candida parapsilosis, C. orthopsilosis and C. metapsilosis. A total of 103 isolates, including reference strains and clinical isolates, were identified by pyrosequencing of the ITS1 region and then assay by MALDI-TOF mass spectrometry. Concordance between the two methods was 100%, showing that MALDI-TOF may be useful as a rapid and reliable method for discrimination of species within the C. parapsilosis group.

Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers.

BACKGROUND: The programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies. PATIENTS AND METHODS: This phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged ≥18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR ≤20% was not of interest for development as monotherapy, and NPR ≥40% was defined as the threshold of benefit/success. If ≥3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated. RESULTS: Overall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively. CONCLUSIONS: Atezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings.