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BACKGROUND & AIMS: In the global, phase III HIMALAYA study in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) vs. sorafenib; durvalumab was noninferior to sorafenib. HBV is the predominant HCC aetiology in most of Asia vs. HCV or nonviral aetiologies in Western countries and Japan. This analysis evaluated safety and efficacy outcomes for STRIDE and durvalumab monotherapy vs. sorafenib, in HIMALAYA participants enrolled in Asia, excluding Japan. METHODS: In HIMALAYA, participants were randomised to STRIDE, durvalumab, or sorafenib. The Asian subgroup in this analysis included participants enrolled in Hong Kong, India, South Korea, Taiwan, Thailand, and Vietnam. OS, objective response rate (ORR; per Response Evaluation Criteria in Solid Tumors, version 1.1), and safety were assessed in the Asian subgroup and in an exploratory subgroup of participants in Hong Kong and Taiwan. RESULTS: The Asian subgroup included 479 participants randomised to STRIDE (n=156), durvalumab (n=167), or sorafenib (n=156). OS was improved for STRIDE vs. sorafenib (HR 0.68; 95% CI 0.52-0.89]). The OS HR for durvalumab vs. sorafenib was 0.83 (95% CI 0.64-1.06). In Hong Kong and Taiwan (n=141), OS HRs for STRIDE vs. sorafenib and durvalumab vs. sorafenib were 0.44 (95% CI 0.26-0.77) and 0.64 (95% CI 0.37-1.08), respectively. In the Asian subgroup, ORR (including unconfirmed responses) was numerically higher for STRIDE (28.2%) and durvalumab (18.6%) vs. sorafenib (9.0%), and Grade 3/4 treatment-related adverse events were numerically lower for STRIDE (19.9%) and durvalumab (13.3%) vs. sorafenib (30.5%). CONCLUSIONS: STRIDE improved outcomes vs. sorafenib in the Asian subgroup. These results support the benefits of STRIDE for participants with uHCC globally, including the Asia-Pacific region. CLINICAL TRIAL NUMBER: NCT03298451 IMPACT AND IMPLICATIONS: The global, phase III HIMALAYA study found that the STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen improved overall survival (OS), including long-term OS, vs. sorafenib, and that durvalumab monotherapy was noninferior to sorafenib in participants with unresectable hepatocellular carcinoma (uHCC). However, there are differences in the aetiology and clinical practices related to HCC in parts of Asia, compared to Western countries and Japan, which could lead to differences in treatment outcomes between these regions. The results of this analysis demonstrate the benefits of STRIDE for participants in the Asia-Pacific region, consistent with the full, global study population. Overall, these findings continue to support the use of STRIDE in a diverse population, reflective of uHCC globally.
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BACKGROUND AND AIMS: The treatment of hepatocellular carcinoma (HCC) has been transformed by the use of immune checkpoint inhibitors. However, most patients with HCC do not benefit from treatment with immunotherapy. There is an urgent need to understand the mechanisms that underlie response or resistance to immunotherapy for patients with HCC. The use of syngeneic mouse models that closely recapitulate the heterogeneity of human HCC will provide opportunities to examine the complex interactions between cancer cells and nonmalignant cells in the tumor microenvironment. APPROACH AND RESULTS: We leverage a multifaceted approach that includes imaging mass cytometry and suspension cytometry by time of flight to profile the tumor microenvironments of the Hep53.4, Hepa 1-6, RIL-175, and TIBx (derivative of TIB-75) syngeneic mouse HCC models. The immune tumor microenvironments vary across these four models, and various immunosuppressive pathways exist at baseline in orthotopic liver tumors derived from these models. For instance, TIBx, which is resistant to anti-programmed cell death protein 1 therapy, contains a high proportion of "M2-like" tumor-associated macrophages with the potential to diminish antitumor immunity. Investigation of The Cancer Genome Atlas reveals that the baseline immunologic profiles of Hep53.4, RIL-175, and TIBx are broadly representative of human HCCs; however, Hepa 1-6 does not recapitulate the immune tumor microenvironment of the vast majority of human HCCs. CONCLUSIONS: There is a wide diversity in the immune tumor microenvironments in preclinical models and in human HCC, highlighting the need to use multiple syngeneic HCC models to improve the understanding of how to treat HCC through immune modulation.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Humanos , Ratones , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Inmunoterapia/métodos , Neoplasias Hepáticas/patología , Microambiente Tumoral , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
Multidisciplinary care has been associated with improved survival in patients with primary liver cancers. We report the practice patterns and real world clinical outcomes for patients presenting to the Johns Hopkins Hospital (JHH) multidisciplinary liver clinic (MDLC). We analyzed hepatocellular carcinoma (HCC, n = 100) and biliary tract cancer (BTC, n = 76) patients evaluated at the JHH MDLC in 2019. We describe the conduct of the clinic, consensus decisions for patient management based on stage categories, and describe treatment approaches and outcomes based on these categories. We describe subclassification of BCLC stage C into 2 parts, and subclassification of cholangiocarcinoma into 4 stages. A treatment consensus was finalized on the day of MDLC for the majority of patients (89% in HCC, 87% in BTC), with high adherence to MDLC recommendations (91% in HCC, 100% in BTC). Among patients presenting for a second opinion regarding management, 28% of HCC and 31% of BTC patients were given new therapeutic recommendations. For HCC patients, at a median follow up of 11.7 months (0.7-19.4 months), median OS was not reached in BCLC A and B patients. In BTC patients, at a median follow up of 14.2 months (0.9-21.1 months) the median OS was not reached in patients with resectable or borderline resectable disease, and was 11.9 months in patients with unresectable or metastatic disease. Coordinated expert multidisciplinary care is feasible for primary liver cancers with high adherence to recommendations and a change in treatment for a sizeable minority of patients.
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Instituciones Oncológicas/organización & administración , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Grupo de Atención al Paciente , Anciano , Algoritmos , Femenino , Humanos , Masculino , Pautas de la Práctica en Medicina , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
To evaluate outcomes in patients with right atrial (RA) hepatocellular carcinoma extension treated with transarterial chemoembolization. Eight patients were retrospectively reviewed. Follow-up visits occurred at 4-6 weeks; transarterial chemoembolization was repeated if residual tumor persisted. After transarterial chemoembolization, RA tumor volume reduction was 86% ± 19; α-fetoprotein level showed a reduction of 95%. From RA tumor diagnosis, 3-, 6-, and 12-month overall survival was 100% ± 0, 100% ± 0, and 67% ± 29, respectively. In patients with hepatocellular carcinoma invading the right atrium, transarterial chemoembolization alone or in combination with systemic therapy yields an improved imaging response and may be associated with improved survival.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/terapia , Atrios Cardíacos/diagnóstico por imagen , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: Mitogen-activated protein kinase (MAPK) kinase (MEK) is an integral component of the RAS signaling pathway, one of the most frequently mutated pathways in cancer biology. MEK inhibitors were initially developed to directly target oncogenic signaling, but are recognized to have pleiotropic effects on both tumor cells and lymphocytes. Here, we review the preclinical and clinical evidence that MEK inhibition is immunomodulatory and discuss the potential rationale for combining MEK inhibitors with systemic immunotherapies. RECENT FINDINGS: MEK inhibition may modulate the tumor microenvironment (TME) through direct effects on both tumor cells and immune cells. Despite encouraging evidence that MEK inhibition can reprogram the tumor microenvironment (TME) and augment anti-tumor immunity regardless of KRAS/BRAF status, recent clinical outcome studies combining MEK inhibition with systemic immunotherapy have yielded mixed results. The combination of MEK inhibitors plus systemic immunotherapies has been tolerable, but has thus far failed to demonstrate clear evidence of synergistic clinical activity. These results underscore the need to understand the appropriate therapeutic context for this combination. MEK inhibitors have the potential to inhibit oncogenic signaling and reprogram the tumor immune microenvironment, representing an attractive therapy to combine with systemic immunotherapies. Ongoing preclinical and clinical studies will further clarify the immunomodulatory effects of MEK inhibitors to inform the design of rational therapeutic combinations.
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Inmunoterapia/métodos , MAP Quinasa Quinasa 1/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/uso terapéutico , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Neoplasias/inmunología , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Cholangiocarcinoma is a rare gastrointestinal malignancy that arises within the intrahepatic, perihilar, and/or extrahepatic bile ducts. Individuals with cystic fibrosis are at increased risk for gastrointestinal malignancies. The most common gastrointestinal malignancy in cystic fibrosis is colon cancer, but other gastrointestinal malignancies also occur at greater rates than the general population. CASE PRESENTATION: We present a case of a rapidly progressive metastatic intrahepatic cholangiocarcinoma in an individual with cystic fibrosis who was 5 months postpartum, incidentally found while undergoing a lung transplantation evaluation. CONCLUSION: A heightened clinical awareness of gastrointestinal malignancies, beyond colon cancer, in individuals with cystic fibrosis is warranted. It remains unclear if pregnancy is an additional risk factor for gastrointestinal malignancies in cystic fibrosis.
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Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/patología , Fibrosis Quística/complicaciones , Adulto , Resultado Fatal , Femenino , Humanos , Hallazgos Incidentales , Metástasis de la Neoplasia , Periodo PospartoRESUMEN
Immune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi-AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range [IQR], 22-110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2-12.9 g/dL) and 6.3 g/dL (IQR, 6.1-8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi-AIHA were similar in DAT positive and negative patients. ICPi-AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi-AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first-line treatment in the majority of patients with ICPi-AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.
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Anemia Hemolítica Autoinmune , Hemoglobinas/metabolismo , Terapia de Inmunosupresión , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia Hemolítica Autoinmune/sangre , Anemia Hemolítica Autoinmune/terapia , Femenino , Glucocorticoides , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Cholangiocarcinoma is an aggressive malignancy with limited therapeutic options. MEK inhibition and antiangiogenic therapies have individually shown modest activity in advanced cholangiocarcinoma, whereas dual inhibition of these pathways has not been previously evaluated. We evaluated the safety and efficacy of combination therapy with the oral VEGF receptor tyrosine kinase inhibitor pazopanib plus the MEK inhibitor trametinib in patients with advanced cholangiocarcinoma. METHODS: In this open-label, multicentre, single-arm trial, adults with advanced unresectable cholangiocarcinoma received pazopanib 800 mg daily and trametinib 2 mg daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) with secondary end points including overall survival (OS), response rate, and disease control rate (DCR). RESULTS: A total of 25 patients were enrolled and had received a median of 2 prior systemic therapies (range 1-7). Median PFS was 3.6 months (95% CI: 2.7-5.1) and the 4-month PFS was 40% (95% CI: 24.7-64.6%). There was a trend towards increased 4-month PFS as compared with the prespecified null hypothesised 4-month PFS of 25%, but this difference did not reach statistical significance (P=0.063). The median survival was 6.4 months (95% CI: 4.3-10.2). The objective response rate was 5% (95% CI: 0.13-24.9%) and the DCR was 75% (95% CI: 51%, 91%). Grade 3/4 adverse events attributable to study drugs were observed in 14 (56%) and included thrombocytopenia, abnormal liver enzymes, rash, and hypertension. CONCLUSIONS: Although the combination of pazopanib plus trametinib had acceptable toxicity with evidence of clinical activity, it did not achieve a statistically significant improvement in 4-month PFS over the prespecified null hypothesised 4-month PFS.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Erupciones por Medicamentos/etiología , Exantema/inducido químicamente , Femenino , Humanos , Hipertensión/inducido químicamente , Indazoles , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridonas/administración & dosificación , Piridonas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinonas/administración & dosificación , Pirimidinonas/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Tasa de Supervivencia , Trombocitopenia/inducido químicamenteAsunto(s)
Carcinoma Hepatocelular/cirugía , Procedimientos Quirúrgicos de Citorreducción , Encefalopatía Hepática/cirugía , Hiperamonemia/cirugía , Neoplasias Hepáticas/cirugía , Adulto , Amoníaco/sangre , Carcinoma Hepatocelular/complicaciones , Encefalopatía Hepática/sangre , Encefalopatía Hepática/diagnóstico , Encefalopatía Hepática/etiología , Humanos , Hiperamonemia/sangre , Hiperamonemia/diagnóstico , Hiperamonemia/etiología , Neoplasias Hepáticas/complicaciones , Masculino , Resultado del TratamientoAsunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Mutación , Neoplasias/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor , Análisis Mutacional de ADN , Humanos , Modelos Genéticos , Neoplasias/tratamiento farmacológicoRESUMEN
Neuronal insulin signaling abnormalities have been associated with Alzheimer's disease (AD). However, the specificity of this association and its underlying mechanisms have been unclear. This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging. IRS1-pS(616), IRS1-pS(312) and downstream target Akt-pS(473) measures were most elevated in AD but were also significantly increased in the tauopathies: Pick's disease, corticobasal degeneration and progressive supranuclear palsy. Double immunofluorescence labeling showed frequent co-expression of IRS1-pS(616) with pathologic tau in neurons and dystrophic neurites. To further investigate an association between tau and abnormal serine phosphorylation of IRS1, we examined the presence of abnormal IRS1-pS(616) expression in pathological tau-expressing transgenic mice and demonstrated that abnormal IRS1-pS(616) frequently co-localizes in tangle-bearing neurons. Conversely, we observed increased levels of hyperphosphorylated tau in the high-fat diet-fed mouse, a model of insulin resistance. These results provide confirmation and specificity that abnormal phosphorylation of IRS1 is a pathological feature of AD and other tauopathies, and provide support for an association between insulin resistance and abnormal tau as well as amyloid-ß.
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Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Serina/metabolismo , Tauopatías/patología , Factores de Edad , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Animales , Proteínas de Unión al ADN/metabolismo , Dieta Alta en Grasa/efectos adversos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Fosforilación/genética , Proteinopatías TDP-43/patología , alfa-Sinucleína/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of primary liver cancer that predominantly affects adolescents and young adults with no history of cirrhosis. Surgical resection is a potentially curative treatment option, but the optimal duration of surveillance after a potentially curative surgical resection is not known. Here, we present a case of a patient with FLC who developed a recurrence of FLC nearly two decades after resection of the primary tumor. Although the optimal duration of imaging surveillance for FLC is not known, this case report provides initial evidence that long-term surveillance in patients with FLC who have received curative intent surgery is warranted.
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Importance: The combination of immune checkpoint inhibitors with antiangiogenic agents has revolutionized the treatment landscape of advanced hepatocellular carcinoma (HCC). However, due to rapid publication of new studies that attained their predefined primary end points, a lack of robust cross-trial comparison of first-line therapies, and diverging clinical guidelines, no clear-cut treatment flowchart and sequence of therapies are available. This critical analysis of the recommendations for the management of advanced HCC from the main scientific societies in the US and Europe adopted an integrated approach to provide information on the clinical benefit (overall survival and progression-free survival) and safety profile of these therapies using the European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS) score and an ad hoc network meta-analysis. Observations: There is a major consensus among guidelines that atezolizumab plus bevacizumab has a primacy as the recommended first-line treatment of choice in advanced HCC. On progression after immunotherapy-containing regimens and for patients with contraindications for immunotherapies, most guidelines maintain the established treatment hierarchy, recommending lenvatinib or sorafenib as the preferred options, followed by either regorafenib, cabozantinib, or ramucirumab. Thus far, the first-line immune-based regimen of tremelimumab plus durvalumab has been integrated only in the American Association for the Study of Liver Diseases guidance document and the latest National Comprehensive Cancer Network guidelines and has particular utility for patients with a high risk of gastrointestinal bleeding. Overall, in the first-line setting, both atezolizumab plus bevacizumab and sintilimab plus IBI305 (a bevacizumab biosimilar) and durvalumab plus tremelimumab received the highest ESMO-MCBS score of 5, indicating a substantial magnitude of clinical benefit. In a network meta-analysis, no significant differences in overall survival were found among the various combination regimens. However, the newly reported combination of camrelizumab plus rivoceranib was associated with a significantly higher risk of treatment-related adverse events compared with atezolizumab plus bevacizumab (relative risk, 1.59; 95% CI, 1.25-2.03; P < .001). Conclusions and Relevance: This narrative review found that atezolizumab plus bevacizumab is regarded as the primary standard of care for advanced HCC in the first-line setting. These findings from integrating the recommendations from scientific societies' guidelines for managing advanced HCC along with new data from cross-trial comparisons may aid clinicians in decision-making and guide them through a rapidly evolving and complex treatment landscape.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Bevacizumab/efectos adversos , Neoplasias Hepáticas/tratamiento farmacológico , Inmunoterapia , SorafenibRESUMEN
Surgical therapies in patients with early-stage HCC can afford long-term survival but are often limited by the continued risk of recurrence, underscoring an interest in (neo)adjuvant strategies. Prior attempts at adjuvant therapy using tyrosine kinase inhibitors failed to yield significant improvements in recurrence-free survival or overall survival. Advances in the efficacy of systemic therapy options, including the introduction of immune checkpoint inhibitors, have fueled renewed interest in this area. Indeed, the IMBrave050 trial recently demonstrated significant improvements in recurrence-free survival with 1 year of adjuvant atezolizumab plus bevacizumab in high-risk patients undergoing surgical resection or ablation, with several other ongoing trials in this space. There is a strong rationale for consideration of the administration of these therapies in the neoadjuvant setting, supported by early clinical data demonstrating high rates of objective responses, although larger trials examining downstream outcomes are necessary, particularly considering the possible risks of this strategy. In parallel, there has been increased interest in using systemic therapies as a bridging or downstaging strategy for liver transplantation. Current data suggest the short-term safety of this approach, with acceptable rates of rejection, so immunotherapy is not considered a contraindication to transplant; however, larger studies are needed to evaluate the incremental value of this approach over locoregional therapy. Conversely, the use of immunotherapy is currently discouraged after liver transplantation, given the high risk of graft rejection and death. The increasing complexity of HCC management and increased consideration of (neo)adjuvant strategies highlight the critical role of multidisciplinary care when making these decisions.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Terapia Neoadyuvante , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamiento farmacológico , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamiento farmacológico , Quimioterapia Adyuvante , Trasplante de Hígado , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of effective systemic therapies, particularly those involving immune-checkpoint inhibitors (ICIs), has substantially improved the outcomes of patients with advanced-stage HCC. Approximately 30% of patients are diagnosed with early stage disease and currently receive potentially curative therapies, such as resection, liver transplantation or local ablation, which result in median overall survival durations beyond 60 months. Nonetheless, up to 70% of these patients will have disease recurrence within 5 years of resection or local ablation. To date, the results of randomized clinical trials testing adjuvant therapy in patients with HCC have been negative. This major unmet need has been addressed with the IMbrave 050 trial, demonstrating a recurrence-free survival benefit in patients with a high risk of relapse after resection or local ablation who received adjuvant atezolizumab plus bevacizumab. In parallel, studies testing neoadjuvant ICIs alone or in combination in patients with early stage disease have also reported efficacy. In this Review, we provide a comprehensive overview of the current approaches to manage patients with early stage HCC. We also describe the tumour immune microenvironment and the mechanisms of action of ICIs and cancer vaccines in this setting. Finally, we summarize the available evidence from phase II/III trials of neoadjuvant and adjuvant approaches and discuss emerging clinical trials, identification of biomarkers and clinical trial design considerations for future studies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Inmunoterapia/métodos , Microambiente TumoralRESUMEN
Due to the lack of treatment options, there remains a need to advance new therapeutics in hepatocellular carcinoma (HCC). The traditional approach moves from initial molecular discovery through animal models to human trials to advance novel systemic therapies that improve treatment outcomes for patients with cancer. Computational methods that simulate tumors mathematically to describe cellular and molecular interactions are emerging as promising tools to simulate the impact of therapy entirely in silico, potentially greatly accelerating delivery of new therapeutics to patients. To facilitate the design of dosing regimens and identification of potential biomarkers for immunotherapy, we developed a new computational model to track tumor progression at the organ scale while capturing the spatial heterogeneity of the tumor in HCC. This computational model of spatial quantitative systems pharmacology was designed to simulate the effects of combination immunotherapy. The model was initiated using literature-derived parameter values and fitted to the specifics of HCC. Model validation was done through comparison with spatial multiomics data from a neoadjuvant HCC clinical trial combining anti-PD1 immunotherapy and a multitargeted tyrosine kinase inhibitor cabozantinib. Validation using spatial proteomics data from imaging mass cytometry demonstrated that closer proximity between CD8 T cells and macrophages correlated with nonresponse. We also compared the model output with Visium spatial transcriptomics profiling of samples from posttreatment tumor resections in the clinical trial and from another independent study of anti-PD1 monotherapy. Spatial transcriptomics data confirmed simulation results, suggesting the importance of spatial patterns of tumor vasculature and TGFß in tumor and immune cell interactions. Our findings demonstrate that incorporating mathematical modeling and computer simulations with high-throughput spatial multiomics data provides a novel approach for patient outcome prediction and biomarker discovery. Significance: Incorporating mathematical modeling and computer simulations with high-throughput spatial multiomics data provides an effective approach for patient outcome prediction and biomarker discovery.
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Biomarcadores de Tumor , Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Humanos , Anilidas/uso terapéutico , Anilidas/farmacología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Ensayos Clínicos como Asunto , Simulación por Computador , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Multiómica , Piridinas/uso terapéutico , Piridinas/farmacología , Microambiente Tumoral/inmunologíaRESUMEN
PURPOSE: To evaluate the potential of volumetric imaging in predicting survival of advanced hepatocellular carcinoma (HCC) patients receiving immunotherapy. METHODS: Retrospective analysis included 40 patients with advanced HCC who received targeted immunotherapy. Baseline and follow-up contrast-enhanced abdominal computed tomography (CT) scans were analyzed. The largest tumor was chosen as the index lesion. Viable tumor volume (qViable) and percentage tumor viability (%Viability) were calculated. Response Evaluation Criteria in Solid Tumors (RECIST) and Tumor volume change after treatment (qRECIST) were measured. Associations with overall survival (OS) were assessed. Cox regression analysis assessed the association between variables and overall survival (OS). A new prognostic stratification system was attempted to categorize patients based on significant predictors of OS. Patients with a baseline %viability > 69% and %viability reduction ≥ 8% were classified as better prognosis. Patients were stratified into better, intermediate and worse prognosis groups based on baseline %viability > 69% and ≥ 8% %viability reduction (better prognosis); baseline %viability ≤ 69% and < 8% %viability reduction (worse prognosis); remainder were intermediate prognosis. RESULTS: Patients with baseline %Viability > 69% and %Viability reduction ≥ 8% showed significantly higher OS. Multivariate analysis confirmed %Viability and %Viability reduction as significant predictors of OS. A prognostic stratification system using these parameters stratified patients into better, intermediate and worse prognosis groups, with the better prognosis showing highest OS. Most patients (97.5%) had stable disease by RECIST while the prognostic model re-classified 47.5% as better prognosis, 37.5% intermediate prognosis, and 15% worse prognosis. CONCLUSION: Volumetric parameters of %Viability and %Viability reduction predict OS in HCC patients undergoing immunotherapy.
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Carcinoma Hepatocelular , Medios de Contraste , Inmunoterapia , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Inmunoterapia/métodos , Pronóstico , Anciano , Tomografía Computarizada por Rayos X/métodos , Carga Tumoral , Adulto , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de Supervivencia , Valor Predictivo de las PruebasRESUMEN
Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.