Sherrie Bhoori

Immunotherapy (IT) with immune-checkpoint inhibitors is becoming a universal strategy for cancer treatment. However, most solid malignancies require the combination of IT with standard therapies to achieve consistent clinical benefit. Nevertheless, the synergistic mechanisms underlying the efficacy of these different combinatorial regimens, particularly in term of immunological outcomes, are still poorly defined. IT should be combined with other oncological treatments based on a scientifically-sounded rationale to possibly potentiate, and not jeopardize, the IT-mediated priming of anti-tumor immunity. An extreme example of this concept is represented by hepatocellular carcinoma (HCC), in which IT is starting to be administered with liver transplantation (LT). Indeed, such a combination has been considered in recent clinical studies with rather promising results in terms of efficacy. Notwithstanding, the immunosuppressive regimens required for avoiding graft rejection could heavily penalize T cell responses induced by IT. Hence, how could such a combination therapy be clinically effective? This is the topic we have been recently addressing with the ImmunoXXL study (NCT05879328), a prospective clinical trial in which multimodal immunomonitoring has been applied to HCC patients undergoing IT+LT or receiving the two regimens alone. Data obtained so far suggest the occurrence of an unexpected immune synergism based on the ability of LT to sustain IT-primed T cell memory through the engagement of trained immunity, thus shedding light on the rationale of transplant oncology in solid tumors.

Background: Systemic immunosuppression characterizing cancer patients represents a concern regarding the efficacy of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, and real-world evidence is needed to define the efficacy and the dynamics of humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines. Methods: We conducted an observational study that included patients with solid tumors who were candidates for mRNA anti-SARS-CoV-2 vaccination at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. The primary objective was to monitor the immunologic response to the mRNA anti-SARS-CoV-2 vaccination in terms of anti-spike antibody levels. All the patients received two doses of the mRNA-1273 vaccine or the BNT162b2 vaccine. Healthcare workers served as a control group of healthy subjects. Results: Among the 243 patients included in the present analysis, 208 (85.60%) and 238 (97.94%) resulted seroconverted after the first and the second dose of vaccine, respectively. Only five patients (2.06%) had a negative titer after the second dose. No significant differences in the rate of seroconversion after two vaccine doses were observed in patients as compared with the control group of healthy subjects. Age and anticancer treatment class had an independent impact on the antibody titer after the second dose of vaccination. In a subgroup of 171 patients with available data about the third timepoint, patients receiving immunotherapy with immune checkpoint inhibitors seem to have a higher peak of antibodies soon after the second dose (3 weeks after), but a more pronounced decrease at a late timepoint (3 months after). Conclusions: The systemic immunosuppression characterizing cancer patients did not seem to dramatically affect the humoral response to anti-SARS-CoV-2 mRNA vaccines in our population of patients with solid tumors. Further investigation is needed to dissect the interplay between immunotherapy and longitudinal dynamics of humoral response to mRNA vaccines, as well as to analyze the cellular response to mRNA vaccines in cancer patients.

A comprehensive longitudinal molecular study of resistance mechanisms for IO in a MSI-H CCA patient.

Wilson’s disease (WD) is a rare genetic disorder with protean manifestations. Even if liver transplantation (LT) could represent an effective therapeutic option for patients with end‐stage liver disease, it has remained controversial in the presence of neuropsychiatric involvement. This study aimed to examine the frequency of adult LT for WD in Italy, focusing on the disease phenotype at the time of LT. A retrospective, observational, multicenter study was conducted across Italy exploring the frequency and characteristics of adults transplanted for WD between 2006 and 2016. A total of 29 adult WD patients underwent LT during the study period at 11 Italian LT centers (accounting for 0.4% of all LTs performed), and 27 of them were considered in this analysis (male/female, n = 9/18; age at LT, 29 years [19‐60 years]; median Model for End‐Stage Liver Disease score at LT, 27 [6‐49]). Isolated hepatic phenotype was the indication for LT in 17 (63%) patients, whereas 2 (7%) patients underwent LT for neurological impairment on compensated liver disease. Overall 1‐ and 5‐year patient survival was excellent (88% and 83%, respectively). Neuropsychiatric symptoms early after LT completely recovered in only a few patients. In conclusion, WD remains an uncommon, unusual indication for LT in Italy, displaying good post‐LT graft and patient survival. Because isolated neuropsychiatric involvement represents a rare indication to LT, more data are needed to properly assess the value of LT for WD in this subset of patients.

Background & Aims: Hepatitis C virus (HCV) re‐infection following liver transplant (LT) is associated with reduced graft and patient survival. Before transplant, Sofosbuvir/Ribavirin (SOF/R) treatment prevents recurrent HCV in 96% of those patients achieving viral suppression for at least 4 weeks before transplant. We evaluated whether a bridging SOF‐regimen from pre‐ to post‐transplant is safe and effective to prevent HCV recurrence in those patients with less than 4 weeks of HCV‐RNA undetectability at the time of transplant.Methods: From July 2014 SOF/R was given in 233 waitlisted HCV cirrhotics with/without hepatocellular carcinoma (HCC) within an Italian Compassionate Program. One hundred patients were transplanted and 31 patients (31%) treated with SOF/R bridging therapy were studied.Results: Liver transplant indication in bridge subgroup was HCC in 22 and decompensated cirrhosis in 9. HCV‐genotype was 1/4 in 18 patients. SOF 400 mg/day and R (median dosage 800 mg/day) were given for a median of 35 days before LT. At transplant time, 19 patients were still HCV‐RNA positive (median HCV‐RNA 58 IU/mL). One recipient had a virological breakthrough at week 4 post‐transplant; one died, on treatment, 1‐month post‐transplant for sepsis and 29/31 achieved a 12‐week sustained virological response (94%). Acute cellular rejection occurred in three recipients. On September 2016, 30 recipients (97%) were alive with a median follow‐up of 18 months (range 13‐25).Conclusions: In patients with suboptimal virological response at LT, a bridging SOF/R regimen helps avoiding post‐transplant graft reinfection.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality and is currently the main cause of death in patients with cirrhosis.¹ Liver resection is the first therapeutic option in patients with early tumors and well-preserved liver function.^2-4 In the past 2 decades, a significant improvement in the perioperative management of HCC has occurred, with a parallel reduction of resection-related mortality from 10% and 20% to a near-zero rate in referral centers.^3,5,6 Despite this reduction, liver resection for HCC is still burdened by potentially life-threatening complications, among which liver decompensation (LD) remains the most fearsome and least effectively treated.

Trans-arterial radioembolization (TARE) is a recognized, although not explicitly recommended, experimental therapy for unresectable hepatocellular carcinoma (HCC).