RESUMO
Recent studies highlight the importance of baseline functional immunity for immune checkpoint blockade therapies. High-dimensional systemic immune profiling is performed in a cohort of non-small-cell lung cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders show high baseline myeloid phenotypic diversity in peripheral blood. To quantify it, we define a diversity index as a potential biomarker of response. This parameter correlates with elevated activated monocytic cells and decreased granulocytic phenotypes. High-throughput profiling of soluble factors in plasma identifies fractalkine (FKN), a chemokine involved in immune chemotaxis and adhesion, as a biomarker of response to immunotherapy that also correlates with myeloid cell diversity in human patients and murine models. Secreted FKN inhibits lung adenocarcinoma growth in vivo through a prominent contribution of systemic effector NK cells and increased tumor immune infiltration. FKN sensitizes murine lung cancer models refractory to anti-PD-1 treatment to immune checkpoint blockade immunotherapy. Importantly, recombinant FKN and tumor-expressed FKN are efficacious in delaying tumor growth in vivo locally and systemically, indicating a potential therapeutic use of FKN in combination with immunotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Antígeno B7-H1/genética , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimiocina CX3CL1/genética , Quimiocina CX3CL1/uso terapêutico , Neoplasias Pulmonares/genéticaRESUMO
BACKGROUND: Previous studies have shown that functional systemic immunity is required for the efficacy of PD-1/PD-L1 blockade immunotherapies in cancer. Hence, systemic reprogramming of immunosuppressive dysfunctional myeloid cells could overcome resistance to cancer immunotherapy. METHODS: Reprogramming of tumour-associated myeloid cells with oleuropein was studied by quantitative differential proteomics, phenotypic and functional assays in mice and lung cancer patients. Combinations of oleuropein and two different delivery methods of anti-PD-1 antibodies were tested in colorectal cancer tumour models and in immunotherapy-resistant lung cancer models. RESULTS: Oleuropein treatment reprogrammed monocytic and granulocytic myeloid-derived suppressor cells, and tumour-associated macrophages towards differentiation of immunostimulatory subsets. Oleuropein regulated major differentiation programmes associated to immune modulation in myeloid cells, which potentiated T cell responses and PD-1 blockade. PD-1 antibodies were delivered by two different strategies, either systemically or expressed within tumours using a self-amplifying RNA vector. Combination anti-PD-1 therapies with oleuropein increased tumour infiltration by immunostimulatory dendritic cells in draining lymph nodes, leading to systemic antitumour T cell responses. Potent therapeutic activities were achieved in colon cancer and lung cancer models resistant to immunotherapies, even leading to complete tumour regression. DISCUSSION: Oleuropein significantly improves the outcome of PD-1/PD-L1 blockade immunotherapy strategies by reprogramming myeloid cells.
Assuntos
Antígeno B7-H1 , Glucosídeos Iridoides , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Receptor de Morte Celular Programada 1 , Inibidores de Checkpoint Imunológico/farmacologia , Células Mieloides , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Microambiente TumoralRESUMO
BACKGROUND: Hemovigilance (HV) is usually based on voluntary reports (passive HV). Our aim is to ascertain credible incidence, severity, and mortality of transfusion-associated adverse events (TAAEs) using an active HV program. STUDY DESIGN AND METHODS: Prospective cohort study to estimate transfusion risk after 46,488 transfusions in 5830 patients, using an active HV program with follow-up within the first 24 h after transfusion. We compared these results to those with the previously established passive HV program during the same 30 months of the study. We explored factors associated with the occurrence of TAAEs using generalized estimating equations models. RESULTS: With the active HV program TAAEs incidence was 57.3 (95% CI, 50.5-64.2) and mortality 1.1 (95% CI, 0.13-2.01) per 10,000 transfusions. Incidence with the new surveillance model was 14.0 times higher than with the passive. Most events occurred when transfusions had already finished (60.2%); especially pulmonary events (80.4%). Three out of five deaths and 50.3% of severe TAAEs were pulmonary. In the multivariate analysis surgical patients had half TAAEs risk when compared to medical patients (OR, 0.53; 95% CI, 0.34-0.78) and women had nearly twice the risk of a pulmonary event compared to men (OR, 1.84; 95% CI, 1.03-3.32). Patient's age, blood component type, or blood component shelf-life were unrelated to TAAEs risk. DISCUSSION: Active hemovigilance programs provide additional data which may lead to better recognition and understanding of TAAEs and their frequency and severity.
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Segurança do Sangue , Transfusão de Sangue , Masculino , Humanos , Feminino , Incidência , Estudos Prospectivos , SeguimentosRESUMO
The application of BNT162b2 and mRNA-1273 vaccines against SARS-CoV-2 infection has constituted a determinant resource to control the COVID-19 pandemic. Since the beginning of 2021, millions of doses have been administered in several countries of North and South America and Europe. Many studies have confirmed the efficacy of these vaccines in a wide range of ages and in vulnerable groups of people against COVID-19. Nevertheless, the emergence and selection of new variants have led to a progressive decay in vaccine efficacy. Pfizer-BioNTech and Moderna developed updated bivalent vaccines-Comirnaty and Spikevax-to improve responses against the SARS-CoV-2 Omicron variants. Frequent booster doses with monovalent or bivalent mRNA vaccines, the emergence of some rare but serious adverse events and the activation of T-helper 17 responses suggest the need for improved mRNA vaccine formulations or the use of other types of vaccines. In this review, we discuss the advantages and limitations of mRNA vaccines targeting SARS-CoV-2 focusing on the most recent, related publications.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Vacina BNT162 , Pandemias , Vacinas de mRNA , Vacinas CombinadasRESUMO
Immunotherapies based on immune checkpoint blockade have shown remarkable clinical outcomes and durable responses in patients with many tumor types. Nevertheless, these therapies lack efficacy in most cancer patients, even causing severe adverse events in a small subset of patients, such as inflammatory disorders and hyper-progressive disease. To diminish the risk of developing serious toxicities, intratumor delivery of monoclonal antibodies could be a solution. Encouraging results have been shown in both preclinical and clinical studies. Thus, intratumor immunotherapy as a new strategy may retain efficacy while increasing safety. This approach is still an exploratory frontier in cancer research and opens up new possibilities for next-generation personalized medicine. Local intratumor delivery can be achieved through many means, but an attractive approach is the use of gene therapy vectors expressing mAbs inside the tumor mass. Here, we summarize basic, translational, and clinical results of intratumor mAb delivery, together with descriptions of non-viral and viral strategies for mAb delivery in preclinical and clinical development. Currently, this is an expanding research subject that will surely play a key role in the future of oncology.
Assuntos
Anticorpos Monoclonais , Neoplasias , Humanos , Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico , Imunoterapia/métodos , Medicina de PrecisãoRESUMO
Bispecific antibodies are a promising type of therapy for the treatment of cancer due to their ability to simultaneously inhibit different proteins playing a role in cancer progression. The development in lung cancer has been singularly intense because of the increasingly vast knowledge of the underlying molecular routes, in particular, in oncogene-driven tumors. In this review, we present the current landscape of bispecific antibodies for the treatment of lung cancer and discuss potential scenarios where the role of these therapeutics might expand in the near future.
Assuntos
Anticorpos Biespecíficos , Neoplasias Pulmonares , Humanos , Anticorpos Biespecíficos/uso terapêutico , Neoplasias Pulmonares/patologia , ImunoterapiaRESUMO
BACKGROUND: Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. METHODS: CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. RESULTS: CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. CONCLUSIONS: CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.
Assuntos
Antígenos CD/imunologia , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Antígenos CD/metabolismo , Antígeno B7-H1 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Receptor de Morte Celular Programada 1 , Linfócitos T , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
PD-L1/PD-1 blockade immunotherapy has changed the therapeutic approaches for the treatment of many cancers. Nevertheless, the mechanisms underlying its efficacy or treatment failure are still unclear. Proficient systemic immunity seems to be a prerequisite for efficacy, as recently shown in patients and in mouse models. It is widely accepted that expansion of anti-tumor CD8 T cell populations is principally responsible for anti-tumor responses. In contrast, the role of CD4 T cells has been less studied. Here we review and discuss the evidence supporting the contribution of CD4 T cells to anti-tumor immunity, especially recent advances linking CD4 T cell subsets to efficacious PD-L1/PD-1 blockade immunotherapy. We also discuss the role of CD4 T cell memory subsets present in peripheral blood before the start of immunotherapies, and their utility as predictors of response.
Assuntos
Antígeno B7-H1 , Imunoterapia , Neoplasias , Animais , Camundongos , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD4-Positivos , Fatores Imunológicos , Imunoterapia/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Subpopulações de Linfócitos TRESUMO
Vaccination, being able to prevent millions of cases of infectious diseases around the world every year, is the most effective medical intervention ever introduced. However, immunosenescence makes vaccines less effective in providing protection to older people. Although most studies explain that this is mainly due to the immunosenescence of T and B cells, the immunosenescence of innate immunity can also be a significant contributing factor. Alterations in function, number, subset, and distribution of blood neutrophils, monocytes, and natural killer and dendritic cells are detected in aging, thus potentially reducing the efficacy of vaccines in older individuals. In this paper, we focus on the immunosenescence of the innate blood immune cells. We discuss possible strategies to counteract the immunosenescence of innate immunity in order to improve the response to vaccination. In particular, we focus on advances in understanding the role and the development of new adjuvants, such as TLR agonists, considered a promising strategy to increase vaccination efficiency in older individuals.
Assuntos
Imunossenescência , Vacinas , Adjuvantes Imunológicos , Idoso , Envelhecimento , Humanos , Imunidade Inata , VacinaçãoRESUMO
The number of people that are 65 years old or older has been increasing due to the improvement in medicine and public health. However, this trend is not accompanied by an increase in quality of life, and this population is vulnerable to most illnesses, especially to infectious diseases. Vaccination is the best strategy to prevent this fact, but older people present a less efficient response, as their immune system is weaker due mainly to a phenomenon known as immunosenescence. The adaptive immune system is constituted by two types of lymphocytes, T and B cells, and the function and fitness of these cell populations are affected during ageing. Here, we review the impact of ageing on T and B cells and discuss the approaches that have been described or proposed to modulate and reverse the decline of the ageing adaptive immune system.
Assuntos
Imunossenescência , Imunidade Adaptativa , Idoso , Envelhecimento , Humanos , Qualidade de Vida , VacinaçãoRESUMO
Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule comparable to PD-1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. LAG-3 is the third inhibitory receptor to be exploited in human anti-cancer immunotherapies, and it is considered a potential next-generation cancer immunotherapy target in human therapy, right next to PD-1 and CTLA-4. Unlike PD-1 and CTLA-4, the exact mechanisms of action of LAG-3 and its relationship with other immune checkpoint molecules remain poorly understood. This is partly caused by the presence of non-conventional signaling motifs in its intracellular domain that are different from other conventional immunoregulatory signaling motifs but with similar inhibitory activities. Here we summarize the current understanding of LAG-3 signaling and its role in LAG-3 functions, from its mechanisms of action to clinical applications.
Assuntos
Antígenos CD/metabolismo , Antígenos CD/fisiologia , Transdução de Sinais/fisiologia , Humanos , Imunoterapia , Ativação Linfocitária , Neoplasias/metabolismo , Receptores Imunológicos/metabolismo , Linfócitos T/imunologia , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
Along with the positioning of immunotherapy as a preferential treatment for a wide variety of neoplasms, a new pattern of response consisting in a sudden acceleration of tumor growth has been described. This phenomenon has received the name of "hyperprogressive disease", and several definitions have been proposed for its identification, most of them relying on radiological criteria. However, due to the fact that the cellular and molecular mechanisms have not been elucidated yet, there is still some debate regarding whether this fast progression is induced by immunotherapy or only reflects the natural course of some highly aggressive neoplasms. Moreover, contradictory results of trials including patients with different cancer types suggest that both the incidence, the associated factors and the implications regarding prognosis might differ depending on tumor histology. This article intends to review the main publications regarding this matter and critically approach the most controversial aspects.
Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/imunologia , Neoplasias/terapia , PrognósticoRESUMO
The development of cancer immunotherapy in the last decade has followed a vertiginous rhythm. Nowadays, immune checkpoint inhibitors (ICI) which include anti-CTLA4, anti-PD-1 and anti-PD-L1 antibodies are in clinical use for the treatment of numerous cancers. However, approximately only a third of the patients benefit from ICI therapies. Many efforts have been made for the identification of biomarkers allowing patient stratification into potential responders and progressors before the start of ICI therapies or for monitoring responses during treatment. While much attention is centered on biomarkers from the tumor microenvironment, in many cases biopsies are not available. The identification of systemic immune cell subsets that correlate with responses could provide promising biomarkers. Some of them have been reported to influence the response to ICI therapies, such as proliferation and activation status of CD8 and CD4 T cells, the expression of immune checkpoints in peripheral blood cells and the relative numbers of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. In addition, the profile of soluble factors in plasma samples could be associated to response or tumor progression. Here we will review the cellular subsets associated to response or progression in different studies and discuss their accuracy in diagnosis.
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Biomarcadores , Células Sanguíneas , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Antígeno CTLA-4 , Humanos , Imunoterapia , Células Matadoras Naturais , Macrófagos , Monócitos , Células Supressoras Mieloides/metabolismo , Neoplasias/tratamento farmacológico , Microambiente Tumoral/imunologiaRESUMO
The use of monoclonal antibodies targeting PD-1/PD-L1 axis completely changed anticancer treatment strategies. However, despite the significant improvement in overall survival and progression-free survival of patients undergoing these immunotherapy treatments, the only clinically accepted biomarker with some prediction capabilities for the outcome of the treatment is PD-L1 expression in tumor biopsies. Nevertheless, even when having PD-L1-positive tumors, numerous patients do not respond to these treatments. Considering the high cost of these therapies and the risk of immune-related adverse events during therapy, it is necessary to identify additional biomarkers that would facilitate stratifying patients in potential responders and non-responders before the start of immunotherapies. Here, we review the utility of PD-L1 expression not only in tumor cells but in immune system cells and their influence on the antitumor activity of immune cell subsets.
Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Animais , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Humanos , Imunoterapia/efeitos adversos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismoRESUMO
PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blockade anticancer therapies, particularly for lung cancer. However, the reliability of this marker is still under debate. Moreover, PD-L1 is widely expressed by many immune cell types, and little is known on the relevance of systemic PD-L1⺠cells for responses to immune checkpoint blockade. We present two clinical cases of patients with non-small cell lung cancer (NSCLC) and PD-L1-negative tumors treated with atezolizumab that showed either objective responses or progression. These patients showed major differences in the distribution of PD-L1 expression within systemic immune cells. Based on these results, an exploratory study was carried out with 32 cases of NSCLC patients undergoing PD-L1/PD-1 blockade therapies, to compare PD-L1 expression profiles and their relationships with clinical outcomes. Significant differences in the percentage of PD-L1⺠CD11b⺠myeloid cell populations were found between objective responders and non-responders. Patients with percentages of PD-L1⺠CD11b⺠cells above 30% before the start of immunotherapy showed response rates of 50%, and 70% when combined with memory CD4 T cell profiling. These findings indicate that quantification of systemic PD-L1⺠myeloid cell subsets could provide a simple biomarker for patient stratification, even if biopsies are scored as PD-L1 null.
Assuntos
Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Many cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance.
Assuntos
Antígenos CD , Imunoterapia , Proteína do Gene 3 de Ativação de Linfócitos , Receptor de Morte Celular Programada 1 , Proteínas Proto-Oncogênicas c-cbl , Transdução de Sinais , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Proteínas Proto-Oncogênicas c-cbl/genética , Imunoterapia/métodos , Transdução de Sinais/efeitos dos fármacos , Antígenos CD/metabolismo , Antígenos CD/genética , Animais , Camundongos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linhagem Celular Tumoral , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologiaRESUMO
BACKGROUND: Identification of predictive biomarkers to Immune checkpoint inhibitors (ICIs) in head and neck cancer (HNSCC) is an unmet need. METHODS: This was a prospective observational study including 25 patients with HNSCC treated with immunotherapy or chemotherapy after a prior platinum-based regimen. Low density neutrophils (LDNs) and serum markers were analyzed. RESULTS: In the immunotherapy cohort, patients with high LDN levels had a shorter progression free survival (PFS) (1.8 months vs. 10.9 months; *p = 0.034). Also, progressors showed higher percentage of LDNs compared to non-progressors although significance was not reached (mean 20.68% vs. 4.095%, p = 0.0875). These findings were not replicated in patients treated with chemotherapy. High levels of interleukin-7 (IL7) were correlated with a significantly longer overall survival (OS) (13.47 months 3.51 vs. months, *p = 0.013). CONCLUSIONS: High baseline circulating LDNs and low IL7 could identify a subset of patients intrinsically refractory to ICIs as monotherapy in HNSCC.
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Neoplasias de Cabeça e Pescoço , Interleucina-7 , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Neutrófilos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/etiologia , Biomarcadores , Imunoterapia/efeitos adversosRESUMO
Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated melanoma circulating tumor cells rewire lipid metabolism by upregulating fatty acid (FA) transport and FA beta-oxidationârelated genes. In patients with melanoma, high expression of FA transporters and FA beta-oxidation enzymes significantly correlates with reduced progression-free and overall survival. Among the highest expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyltransferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium-chain FAs toward mitochondria to fuel mitochondrial FA beta-oxidation. Knockdown of carnitine O-octanoyltransferase or carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase and carnitine acetyltransferase depletion could be rescued by medium-chain FA supplementation, indicating that the peroxisomal supply of FAs is crucial for the survival of nonadherent melanoma cells. Our study identifies targeting the FA-based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity to challenge melanoma progression. Moreover, the discovery of the antimetastatic activity of the Food and Drug Administrationâapproved drug ranolazine carries translational potential.
Assuntos
Melanoma , Células Neoplásicas Circulantes , Camundongos , Animais , Carnitina O-Acetiltransferase/genética , Carnitina O-Acetiltransferase/metabolismo , Carnitina Aciltransferases/genética , Carnitina Aciltransferases/metabolismo , Ranolazina , Oxirredução , Ácidos Graxos/metabolismo , Melanoma/tratamento farmacológico , Carnitina/metabolismoRESUMO
INTRODUCTION: Belantamab mafodotin (BM) is a new anti-BCMA antibody-drug conjugate, recently approved for triple-class relapsed and refractory multiple myeloma (RRMM). We assessed real-world outcomes with BM in patients under the Spanish Expanded Access Program (EAP). METHODS: We conducted an observational, retrospective, multicenter study including RRMM patients who received ≥ 1 dose of BM (Nov 2019 to Jun 2021). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and incidence of treatment-emergent adverse events (TEAEs). RESULTS: Thirty-three patients were included with a median of 70 years of age (range, 46-79 years). Median time from diagnosis was 71 months (range, 10-858 months). Median prior lines was 5 (range, 3-8 lines); 90% of patients were triple-/quad-/penta-refractory; 48% showed high-risk cytogenetics. Median BM doses was 3 (range 1-16 doses), with a median follow-up of 11 months (6-15 months). ORR was 42.2% (≥ VGPR, 18.2%). Median PFS was 3 months (95% CI 0.92-5.08) in the overall population, and 11 months (HR 0.26; 95% CI 0.10-0.68) for patients who achieved ≥ PR. PFS was not significantly different according to age, cytogenetic risk, and prior therapy lines. OS was 424 days (95% CI 107-740). Non-hematological TEAEs (57.6% of patients; 30.3% ≥ G3) included keratopathy (51.5%; 21.2% ≥ G3) and patient-reported vision-related symptoms (45.5%). Keratopathy was resolved in 70.6% of patients. G3 hematological TEAEs was 18.2%, thrombocytopenia (21.2%). Dose reductions due to TEAEs: 30.3%; delays: 36.4%. Treatment discontinuation causes: progression (54.5%), toxicity (non-ocular; 6%/ocular; 6% /ocular + non-ocular toxicity; 3%), death (6%), and patient's decision (3%). CONCLUSIONS: BM showed relevant anti-myeloma activity in RRMM with a manageable safety profile. These results corroborate those observed in the BM pivotal trial.
RESUMO
Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged BRAF inhibitor (BRAFi) treatment contributes to acquired therapy resistance in mice. Targeting FAO using the US Food and Drug Administration-approved and European Medicines Agency-approved anti-anginal drug ranolazine (RANO) delays tumour recurrence with acquired BRAFi resistance. Single-cell RNA-sequencing analysis reveals that RANO diminishes the abundance of the therapy-resistant NGFRhi neural crest stem cell subpopulation. Moreover, by rewiring the methionine salvage pathway, RANO enhances melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of RANO with anti-PD-L1 antibodies strongly improves survival by increasing antitumour immune responses. Altogether, we show that RANO increases the efficacy of targeted melanoma therapy through its effects on FAO and the methionine salvage pathway. Importantly, our study suggests that RANO could sensitize BRAFi-resistant tumours to immunotherapy. Since RANO has very mild side-effects, it might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma.