Adoptive T cell therapy for solid tumors: current landscape and future challenges.

Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACT modalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors.

SARS-CoV-2 infection in patients with melanoma: results of the Spanish Melanoma Group registry.

BACKGROUND: The Spanish Melanoma Group (GEM) developed a national registry of patients with melanoma infected by SARS-CoV-2 ("GRAVID"). METHODS: The main objective was to describe the COVID-19 fatality rate in patients with melanoma throughout the pandemic, as well as to explore the effect of melanoma treatment and tumor stage on the risk of COVID-19 complications. These are the final data of the register, including cases from February 2020 to September 2021. RESULTS: One hundred-fifty cases were registered. Median age was 68 years (range 6-95), 61 (40%) patients were females, and 63 (42%) patients had stage IV. Thirty-nine (26%) were on treatment with immunotherapy, and 17 (11%) with BRAF-MEK inhibitors. COVID-19 was resolved in 119 cases, including 85 (57%) patients cured, 15 (10%) that died due to melanoma, and 20 (13%) that died due to COVID-19. Only age over 60 years, cardiovascular disorders, and diabetes mellitus increased the risk of death due to COVID-19, but not advanced melanoma stage nor melanoma systemic therapies. Three waves have been covered by the register: February-May 2020, August-November 2020, and December 2020-April 2021. The first wave had the highest number of registered cases and COVID-19 mortality. CONCLUSION: Tumor stage or melanoma treatments are non-significant prognostic factors for COVID-19 mortality. During the pandemic in Spain there was a downward trend in the number of patients registered across the waves, as well as in the severity of the infection. GOV IDENTIFIER: NCT04344002.

Neurologic Toxicity of Immune Checkpoint Inhibitors: A Review of Literature.

Immune checkpoint inhibitors have entailed a change of paradigm in the management of multiple malignant diseases and are acquiring a key role in an increasing number of clinical sceneries. However, since their mechanism of action is not limited to the tumor microenvironment, their systemic activity may lead to a wide spectrum of immune-related side effects. Although neurological adverse events are much less frequent than gastrointestinal, hepatic, or lung toxicity, with an incidence of <5%, their potential severity and consequent interruptions to cancer treatment make them of particular importance. Despite them mainly implying peripheral neuropathies, immunotherapy has also been associated with an increased risk of encephalitis and paraneoplastic disorders affecting the central nervous system, often appearing in a clinical context where the appropriate diagnosis and early management of neuropsychiatric symptoms can be challenging. Although the pathogenesis of these complications is not fully understood yet, the blockade of tumoral inhibitory signals, and therefore the elicitation of cytotoxic T-cell-mediated response, seems to play a decisive role. The aim of this review was to summarize the current knowledge about the pathogenic mechanisms, clinical manifestations, and therapeutic recommendations regarding the main forms of neurotoxicity related to checkpoint inhibitors.

Acute anti-Ma2 paraneoplastic encephalitis associated to pembrolizumab: a case report and review of literature.

Anti-Ma2 encephalitis is a rare neurological disorder with a predominant involvement of brainstem, limbic and diencephalic structures. Although an unspecific encephalopathy is the usual form of presentation, acute-onset neurologic symptoms and other atypical manifestations have been described and account for the challenging diagnosis of this entity. Despite being usually detected as a paraneoplastic syndrome in patients with early-stage tumors or without a previous history of malignancy, a growing concern has arisen from several cases reported in metastatic patients under treatment with immune checkpoint inhibitors. We report what to our knowledge is the first known case of anti-Ma2 encephalitis associated to pembrolizumab and presenting as an acute-onset focal neurological syndrome, consisting on acute global aphasia, right upper limb paresia, hypoacusia, sleep disorder, decreased conscious level and a motor focal status that was refractory to anticonvulsant therapy. A brain MRI scan showed a focal alteration of the cortical-subcortical signal on the left parietal lobe. CSF study found a significant hyperproteinorrhachia and electroencephalography showed lateralized periodic discharges (LPDs), suggestive of a diffuse encephalopathy. A positive result for anti-Ma2 antibodies was obtained both in blood and CSF samples through indirect immune-fluorescence (IFI) and later confirmed by western-blot technique. Our patient obtained a mild response to steroid therapy and a significant improvement after the administration of intravenous immunoglobulins. The hypothesis that checkpoint inhibitors may trigger the expression of previously subclinical paraneoplastic events, through the strengthening of cytotoxic T cells-mediated immune response, is supported by our finding of preexisting anti-Ma2 antibodies in preserved blood samples obtained before the initiation of pembrolizumab in our patient. Further research is needed to reveal if the detection of onconeural antibodies prior to a treatment with checkpoint inhibitors may be used as a predictive biomarker of neurologic immune-related high-grade toxicity.

Phase I Trial of Cemiplimab, Radiotherapy, Cyclophosphamide, and Granulocyte Macrophage Colony-Stimulating Factor in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

LESSONS LEARNED: Cemiplimab in combination with radiation therapy, cyclophosphamide, and granulocyte macrophage colony-stimulating factor did not demonstrate efficacy above what can be achieved with other PD-1 inhibitor monotherapies in patients with refractory and metastatic head and neck squamous cell carcinoma. The safety profile of cemiplimab combination therapy was consistent with previously reported safety profiles of cemiplimab monotherapy. No new safety signal was observed. BACKGROUND: Refractory and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) generally does not respond to PD-1 inhibitor monotherapy. Cemiplimab is a human anti-PD-1 monoclonal antibody. An expansion cohort enrolled patients with R/M HNSCC in a phase I study combining cemiplimab plus radiation therapy (RT), cyclophosphamide, and granulocyte macrophage colony-stimulating factor (GM-CSF). METHODS: Patients with R/M HNSCC refractory to at least first-line therapy and for whom palliative RT is clinically indicated received cemiplimab plus RT, cyclophosphamide, and GM-CSF. The co-primary objectives were the safety, tolerability, and efficacy of cemiplimab plus RT, cyclophosphamide, and GM-CSF in 15 patients with R/M HNSCC. RESULTS: Fifteen patients were enrolled. Patients discontinued treatment due to progression of disease. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (40.0%), constipation (26.7%), and asthenia, dyspnea, maculo-papular rash, and pneumonia (each 20%). The only grade ≥3 TEAE that occurred in two patients was pneumonia (13.3%). By investigator assessment, there was one partial response (6.7%); disease control rate was 40.0% (95% confidence interval [CI], 16.3-67.7; five patients with stable disease); seven patients had progressive disease, and two were not evaluable. Median progression-free survival by investigator assessment was 1.8 months (95% CI, 1.7-4.7). CONCLUSION: The regimen demonstrated tolerability but not efficacy above that which can be achieved with anti-PD-1 inhibitor monotherapy for R/M HNSCC.

Cancer immunotherapy in special challenging populations: recommendations of the Advisory Committee of Spanish Melanoma Group (GEM).

Cancer immunotherapy based on the use of antibodies targeting the so-called checkpoint inhibitors, such as programmed cell death-1 receptor, its ligand, or CTLA-4, has shown durable clinical benefit and survival improvement in melanoma and other tumors. However, there are some special situations that could be a challenge for clinical management. Persons with chronic infections, such as HIV-1 or viral hepatitis, latent tuberculosis, or a history of solid organ transplantation, could be candidates for cancer immunotherapy, but their management requires a multidisciplinary approach. The Spanish Melanoma Group (GEM) panel in collaboration with experts in virology and immunology from different centers in Spain reviewed the literature and developed evidence-based guidelines for cancer immunotherapy management in patients with chronic infections and immunosuppression. These are the first clinical guidelines for cancer immunotherapy treatment in special challenging populations. Cancer immunotherapy in chronically infected or immunosuppressed patients is feasible but needs a multidisciplinary approach in order to decrease the risk of complications related to the coexistent comorbidities.

Quality of Life With Pembrolizumab for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: KEYNOTE-040.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) affects health-related quality of life (HRQoL); few treatments have demonstrated clinically meaningful HRQoL benefit. KEYNOTE-040 evaluated pembrolizumab vs standard of care (SOC) in patients with recurrent and/or metastatic HNSCC whose disease recurred or progressed after platinum-containing regimen. METHODS: Patients received pembrolizumab 200 mg or SOC (methotrexate, docetaxel, or cetuximab). Exploratory HRQoL analyses used European Organisation for Research and Treatment of Cancer (EORTC) 30 quality-of-life, EORTC 35-question quality-of-life head and neck cancer-specific module, and EuroQoL 5-dimensions questionnaires. RESULTS: The HRQoL population comprised 469 patients (pembrolizumab = 241, SOC = 228). HRQoL compliance for patients in the study at week 15 was 75.3% (116 of 154) for pembrolizumab and 74.6% (85 of 114) for SOC. The median time to deterioration in global health status (GHS) and QoL scores were 4.8 months with pembrolizumab and 2.8 months with SOC (hazard ratio = 0.79, 95% confidence interval [CI] = 0.59 to 1.05). At week 15, GHS / QoL scores were stable for pembrolizumab (least squares mean [LSM] = 0.39, 95% CI = -3.00 to 3.78) but worsened for SOC (LSM = -5.86, 95% CI = -9.68 to -2.04); the LSM between-group difference was 6.25 points (95% CI = 1.32 to 11.18; nominal 2-sided P = .01). A greater difference in the LSM for GHS / QoL score occurred with pembrolizumab vs docetaxel (10.23, 95% CI = 3.15 to 17.30) compared with pembrolizumab vs methotrexate (6.21, 95% CI = -4.57 to 16.99) or pembrolizumab vs cetuximab (-1.44, 95% CI = -11.43 to 8.56). Pembrolizumab-treated patients had stable functioning and symptoms at week 15, with no notable differences from SOC. CONCLUSIONS: GHS / QoL scores were stable with pembrolizumab but declined with SOC in patients at week 15, supporting the clinically meaningful benefit of pembrolizumab in recurrent and/or metastatic HNSCC.

Melanoma proteomics suggests functional differences related to mutational status.

Melanoma is the most lethal cutaneous cancer. New drugs have recently appeared; however, not all patients obtain a benefit of these new drugs. For this reason, it is still necessary to characterize melanoma at molecular level. The aim of this study was to explore the molecular differences between melanoma tumor subtypes, based on BRAF and NRAS mutational status. Fourteen formalin-fixed, paraffin-embedded melanoma samples were analyzed using a high-throughput proteomics approach, combined with probabilistic graphical models and Flux Balance Analysis, to characterize these differences. Proteomics analyses showed differences in expression of proteins related with fatty acid metabolism, melanogenesis and extracellular space between BRAF mutated and BRAF non-mutated melanoma tumors. Additionally, probabilistic graphical models showed differences between melanoma subgroups at biological processes such as melanogenesis or metabolism. On the other hand, Flux Balance Analysis predicts a higher tumor growth rate in BRAF mutated melanoma samples. In conclusion, differential biological processes between melanomas showing a specific mutational status can be detected using combined proteomics and computational approaches.

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study.

BACKGROUND: There are few effective treatment options for patients with recurrent or metastatic head-and-neck squamous cell carcinoma. Pembrolizumab showed antitumour activity and manageable toxicity in early-phase trials. We aimed to compare the efficacy and safety of pembrolizumab versus standard-of-care therapy for the treatment of head-and-neck squamous cell carcinoma. METHODS: We did a randomised, open-label, phase 3 study at 97 medical centres in 20 countries. Patients with head-and-neck squamous cell carcinoma that progressed during or after platinum-containing treatment for recurrent or metastatic disease (or both), or whose disease recurred or progressed within 3-6 months of previous multimodal therapy containing platinum for locally advanced disease, were randomly assigned (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive pembrolizumab 200 mg every 3 weeks intravenously or investigator's choice of standard doses of methotrexate, docetaxel, or cetuximab intravenously (standard-of-care group). The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT02252042, and is no longer enrolling patients. FINDINGS: Between Dec 24, 2014, and May 13, 2016, 247 patients were randomly allocated to pembrolizumab and 248 were randomly allocated to standard of care. As of May 15, 2017, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 patients in the standard-of-care group had died. Median overall survival in the intention-to-treat population was 8·4 months (95% CI 6·4-9·4) with pembrolizumab and 6·9 months (5·9-8·0) with standard of care (hazard ratio 0·80, 0·65-0·98; nominal p=0·0161). Fewer patients treated with pembrolizumab than with standard of care had grade 3 or worse treatment-related adverse events (33 [13%] of 246 vs 85 [36%] of 234). The most common treatment-related adverse event was hypothyroidism with pembrolizumab (in 33 [13%] patients) and fatigue with standard of care (in 43 [18%]). Treatment-related death occurred in four patients treated with pembrolizumab (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome) and two patients treated with standard of care (malignant neoplasm progression and pneumonia). INTERPRETATION: The clinically meaningful prolongation of overall survival and favourable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Early evolution of BRAFV600 status in the blood of melanoma patients correlates with clinical outcome and identifies patients refractory to therapy.

Serial analysis of BRAF mutations in circulating-free DNA (cfDNA) could be of prognostic value in melanoma patients. We collected blood samples from 63 advanced BRAFV600E/K melanoma patients and determined BRAFV600E/K status in cfDNA using a quantitative 5'-nuclease PCR-based assay. Levels of BRAF mutation in pre-cfDNAs were associated significantly with tumour burden, progression-free survival and overall survival. Changes in BRAF status in cfDNA after initiation of treatment (early-cfDNA) had a significant correlation with outcome. In patients with persistent BRAF mutations (n=12), progression-free survival and overall survival were 3.5 months [95% confidence interval (CI): 1.6-4.6] and 5.3 months (95% CI: 3.4-8.1) compared with 16.6 months (95% CI: 8.2-22.3) and 21.9 months (95% CI: 10.2-NR) in patients with BRAF negativization (n=16), and 15.1 months (95% CI: 2.3-NR) and NR (95% CI: 5.1-NR) in patients who maintained their initial negative status (n=12) (P<0.0001). The median duration of response in patients with radiological response, but persistence of BRAFV600 in early-cfDNA (n=5) was 4 months. Our study indicates that serial BRAF testing in the blood of advanced melanoma identifies patients refractory to therapy.

Predictive factors of response to immunotherapy-a review from the Spanish Melanoma Group (GEM).

Immunotherapy has become a key element in the treatment of several tumors, such as lung carcinoma and melanoma. Immunotherapy, unlike classical chemotherapy and targeted drugs, may yield long-term survival, even in patients who stop treatment due to toxicity. This fact has generated considerable excitement and a real shift in the paradigm of cancer treatment. However, only a small subset of patients benefit from immunotherapy. Survival curves show that most patients have progression of the disease in the first months after starting immunotherapy, followed by a slower decrease over the first 3 years, until curves reach a plateau. This early progression suggests the presence of mechanisms for primary resistance. In addition, some patients have tumor relapse after years of response, suggesting that there is also acquired resistance in a small subset of patients. Resistance mechanisms are now being elucidated. PD-L1 expression in tumor and immune cells correlates with higher chances of response, but melanoma patients with PD-L1 negative tumors can also respond. Several studies have demonstrated an increased probability of clinical benefit when tumors are infiltrated by CD8 T cells, have a high mutation burden or have an interferon gamma signature. But none of these factors has been implemented in the clinical practice, since more studies confirming their value are needed, as well as the development of standardized techniques.

Gastrostomy vs nasogastric tube feeding in patients with head and neck cancer during radiotherapy alone or combined chemoradiotherapy

INTRODUCTION: Patients with head and neck cancer (HNC) submitted to radiotherapy alone or combined chemoradiotherapy present a high prevalence of malnutrition at baseline. Prophylactic use of gastrostomy has been suggested for these patients for delivering enteral nutrition. On the other hand, other authors have failed to demonstrate the effectiveness of this measure over nasogastric tube feeding. MATERIAL AND METHODS: We studied 40 patients with HNC with moderate or severe malnutrition who were offered either prophylactic percutaneous gastrostomy before starting oncologic treatment or close follow-up with nutritional counseling with the placement of a nasogastric tube when necessary. RESULTS: There were no significant changes throughout the study period in weight (p = 0.338), body mass index (BMI) (p = 0.314) or serum proteins (p = 0.729), and these changes showed no differences between the gastrostomy vsnasogastric tube feeding groups. The amount of delivered energy was above the estimated energy needs with both gastrostomy and nasogastric tube feeding, but there were no differences in the total energy provided by enteral nutrition between groups. Patients in the gastrostomy group received enteral nutrition support for a longer period of time (p = 0.007). CONCLUSIONS: Both gastrostomy and nasogastric tube feeding are effective methods of delivering enteral nutrition in patients with HNC submitted to radiotherapy alone or combined chemoradiotherapy, with no differences between them in terms of avoiding further nutritional deterioration.

Gastrostomy vs nasogastric tube feeding in patients with head and neck cancer during radiotherapy alone or combined chemoradiotherapy / Gastrostomía o sonda nasogástrica en pacientes con cáncer de cabeza y cuello durante la radioterapia o tratamiento combinado con quimiorradioterapia

Introduction: Patients with head and neck cancer (HNC) submitted to radiotherapy alone or combined chemoradiotherapy present a high prevalence of malnutrition at baseline. Prophylactic use of gastrostomy has been suggested for these patients for delivering enteral nutrition. On the other hand, other authors have failed to demonstrate the effectiveness of this measure over nasogastric tube feeding. Material and methods: We studied 40 patients with HNC with moderate or severe malnutrition who were offered either prophylactic percutaneous gastrostomy before starting oncologic treatment or close follow-up with nutritional counseling with the placement of a nasogastric tube when necessary. Results: There were no significant changes throughout the study period in weight (p = 0.338), body mass index (BMI) (p = 0.314) or serum proteins (p = 0.729), and these changes showed no differences between the gastrostomy vs nasogastric tube feeding groups. The amount of delivered energy was above the estimated energy needs with both gastrostomy and nasogastric tube feeding, but there were no differences in the total energy provided by enteral nutrition between groups. Patients in the gastrostomy group received enteral nutrition support for a longer period of time (p = 0.007). Conclusions: Both gastrostomy and nasogastric tube feeding are effective methods of delivering enteral nutrition in patients with HNC submitted to radiotherapy alone or combined chemoradiotherapy, with no differences between them in terms of avoiding further nutritional deterioration (AU)

Introducción: los pacientes con cáncer de cabeza y cuello (CCC) que reciben radioterapia o tratamiento combinado con radioterapia y quimioterapia presentan una elevada prevalencia de desnutrición. El uso profiláctico de la gastrostomía se ha sugerido para el soporte nutricional enteral en estos pacientes. Sin embargo, otros autores no han demostrado un beneficio claro de esta medida frente al uso de la sonda nasogástrica. Material y métodos: se realizó el estudio en cuarenta pacientes con CCC con desnutrición moderada o grave, a los cuales se les ofreció la gastrostomía percutánea antes de empezar el tratamiento oncológico o bien seguimiento estrecho mediante consejo nutricional y la colocación de una sonda nasogástrica en el momento necesario. Resultados: no se encontraron cambios significativos en cuanto a peso, (p = 0,338), índice de masa corporal (p = 0,314) o proteínas séricas (p= 0,729) durante el seguimiento, y estos cambios tampoco fueron diferentes entre los pacientes con gastrostomía o con sonda nasogástrica. Las calorías recibidas fueron superiores a los requerimientos estimados en ambos grupos, pero no existieron diferencias entre ellos. Los pacientes con gastrostomía recibieron nutrición enteral durante más tiempo (p = 0,007). Conclusiones: tanto la gastrostomía como la sonda nasogástrica son eficaces para el soporte nutricional enteral en pacientes con CCC que reciben radioterapia o tratamiento combinado con quimioterapia y radioterapia, sin mostrar diferencias en la evolución nutricional entre ambas (AU)

Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study.

The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain.

Treatment patterns of adjuvant interferon-α2b for high-risk melanoma: a retrospective study of the Grupo Español Multidisciplinar de Melanoma - Prima study.

Adjuvant interferon-α2b (IFN-α2b) has been studied extensively in clinical trials, but there have been few studies of real-world use. The aim of this study is to describe the IFN-α2b real-world patterns in patients with high-risk melanoma in Spain. This was a retrospective and multicentre chart review study of an unselected cohort of patients with melanoma at high risk for relapse (stage IIB/IIC/III) treated with IFN-α2b. Patterns were assessed in terms of dose and compliance to planned treatment. A survival analysis was carried out for the full population and according to Kirkwood scheme compliance and the presence of ulceration. Of 327 patients treated with IFN-α2b, 318 received a high-dose regimen following the standard Kirkwood scheme; thus, patterns are described for this regimen. A total of 121 (38%) and 88 (28%) patients had at least one dose reduction during the induction and maintenance phases, respectively. Dose delay was required in fewer than 10% of patients. A total of 78, 40 and 38% of the patients completed the induction phase, maintenance phase and completed treatment, respectively. The median progression-free and overall survival for the full population were 3.2 and 10.5 years, respectively. There were no differences in progression-free survival and overall survival according to Kirkwood scheme compliance and the presence of ulceration. The most frequent adverse events were neutropenia (31%) and fatigue (30%). High-dose IFN-α2b is the most frequently used regimen in Spain as an adjuvant systemic treatment for high-risk melanoma. Despite poor compliance, in this retrospective study, IFN-α2b treatment provided a benefit consistent with that described previously.

Colitis secundaria a ipilimumab: un nuevo reto para el gastroenterólogo / Ipilimumab-induced colitis: A new challenge for gastroenterologists

Existen numerosos fármacos de diversas clases que pueden producir enterocolitis y deberían incluirse siempre en el diagnóstico diferencial de este cuadro clínico. Si ya conocíamos entidades como la colitis asociada a antibióticos o la colitis neutropénica asistimos en la actualidad a un nuevo cuadro de colitis inducida por inmunofármacos. Ipimumab es un anticuerpo monoclonal humanizado que actúa contra la molécula CTLA4, que se encuentra implicada en la regulación de la maduración y activación del linfocito T. Este fármaco ocasiona una activación inmunológica y un efecto antitumoral inmunomediado con excelentes resultados en tumores como el melanoma. Sin embargo, son varios los efectos adversos de tipo inmunomediados que puede producir en distintos órganos, siendo el tubo digestivo uno de los más frecuentes, ocasionando desde una diarrea leve hasta cuadros de colitis con afectación sistémica, perforación intestinal e incluso muertes. Aunque no se han encontrado similitudes en la patogenia con la enfermedad inflamatoria intestinal dada su base inmunológica se han utilizado terapias en correlación con la misma: corticoides e incluso anti-TNF alfa han mostrado eficacia clínica en cuadros moderados y graves. Sin embargo, las pautas de tratamiento anti-TNF no se encuentran definidas ni conocemos su perfil de seguridad. La inclusión de estas nuevas terapias en el tratamiento de diferentes tumores nos obliga a conocer estas entidades y afrontar su manejo como un nuevo reto para el gastroenterólogo. Por este motivo, hemos querido realizar una revisión de la colitis inducida por ipilimumab tratando los aspectos esenciales en la clínica, diagnóstico y terapéutica

Many drugs can produce enterocolitis and they should always be included in the differential diagnosis of this clinical picture. Entities such as antibiotic-associated colitis and neutropenic colitis have been known for some time and recently a new type of drug-induced colitis has emerged due to monoclonal antibodies. Ipimumab is a humanized monoclonal antibody against the CTLA4 molecule that is involved in the maturation and regulation of T lymphocyte activation. This drug causes immune activation and has an immune-mediated antitumor effect with excellent results in tumours such as melanoma. However, several immune-related adverse effects may occur in different organs. The most frequently involved site is the gastrointestinal tract, with adverse effects ranging from mild diarrhea to colitis with systemic involvement, intestinal perforation, and even death. Although no similarities have been found in the pathogenesis with inflammatory bowel disease, treatments have been used in correlation with its autoimmunological profile: anti-TNF alpha corticosteroids have shown clinical efficacy in moderate to severe disease. However the use of anti-TNF treatment has not been defined and the safety profile is unknown. The inclusion of these new therapies in the treatment of several tumours requires familiarity with these entities and their management should be approached as a new challenge for the gastroenterologist. For that reason, we conducted a review of ipilimumab-induced colitis, evaluating essential features of its symptoms, diagnosis and treatment

[Ipilimumab-induced colitis: A new challenge for gastroenterologists]. / Colitis secundaria a ipilimumab: un nuevo reto para el gastroenterólogo.

Many drugs can produce enterocolitis and they should always be included in the differential diagnosis of this clinical picture. Entities such as antibiotic-associated colitis and neutropenic colitis have been known for some time and recently a new type of drug-induced colitis has emerged due to monoclonal antibodies. Ipimumab is a humanized monoclonal antibody against the CTLA4 molecule that is involved in the maturation and regulation of T lymphocyte activation. This drug causes immune activation and has an immune-mediated antitumor effect with excellent results in tumours such as melanoma. However, several immune-related adverse effects may occur in different organs. The most frequently involved site is the gastrointestinal tract, with adverse effects ranging from mild diarrhoea to colitis with systemic involvement, intestinal perforation, and even death. Although no similarities have been found in the pathogenesis with inflammatory bowel disease, treatments have been used in correlation with its autoimmunological profile: anti-TNF alpha corticosteroids have shown clinical efficacy in moderate to severe disease. However the use of anti-TNF treatment has not been defined and the safety profile is unknown. The inclusion of these new therapies in the treatment of several tumours requires familiarity with these entities and their management should be approached as a new challenge for the gastroenterologist. For that reason, we conducted a review of ipilimumab-induced colitis, evaluating essential features of its symptoms, diagnosis and treatment.

Immune checkpoint inhibitors: therapeutic advances in melanoma.

In recent years, new strategies for treating melanoma have been introduced, improving the outlook for this challenging disease. One of the most important advances has been the development of immunotherapy. The better understanding of the role of the immunological system in tumor control has paved the way for strategies to enhance the immune response against cancer cells. Monoclonal antibodies (mAbs) against the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have demonstrated high activity in melanoma and other tumors. Ipilimumab, an anti CTLA-4 antibody, was the first drug of this class that was approved. Although the response rate with ipilimumab is low (less than 20% of patients have objective responses), 20% of patients have long survival, with similar results in the first and second line settings. Nivolumab and pembrolizumab, both anti PD-1 inhibitors, have been approved for the treatment of melanoma, with response rates of 40% and a demonstrated survival advantage in phase III trials. This has marked a new era in the treatment of metastatic melanoma and much research is now ongoing with other drugs targeting checkpoint inhibitors. In addition, the agonist of activating molecules on T cells and their combinations are being investigated. Herein we review the clinical development of checkpoint inhibitors and their approval for treatment of metastatic melanoma.

Endocrinopatías autoinmunitarias inducidas por anticuerpos inmunomoduladores en el tratamiento del cáncer / Autoimmune endocrinopathies induced by immunomodulating antibodies in the treatment of cancer

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