Background Atezolizumab dose selection was supported by linear pharmacokinetics, absence of a maximum tolerated dose, and trough concentrations exceeding the preclinical receptor saturation target. In the Project Optimus era, we explored whether higher body weight-normalized administered dose was associated with improved outcomes in the original phase I dataset. Patients and methods We assessed 660 patients from the first-in-human PCD4989g study (NCT01375842) separately in the dose-escalation (weight-adjusted) and dose-expansion (fixed 1200 mg) cohorts. Patients were grouped as ≤15 or >15 mg/kg. Sensitivity analyses modeled dose continuously and sequentially excluded individual tumor types. Outcomes were overall survival (OS), progression-free survival (PFS), objective response rate, and grouped immune-mediated adverse events. All analyses were exploratory; no equivalence or noninferiority hypothesis was tested. Results In the dose-escalation cohort (N = 431), median OS was 15.4 compared with 16.1 months and median PFS was 2.1 compared with 2.7 months; adjusted models showed no improvement with higher normalized dose. In the fixed-dose cohort (N = 229), median OS was 10.1 compared with 7.4 months and median PFS was 1.4 months in both groups. Higher normalized dose was associated with shorter OS in the multivariable model (hazard ratio 1.679, 95% confidence interval 1.186-2.377) but this attenuated after excluding breast cancer. Pneumonitis was numerically more frequent at >15 mg/kg, although events were sparse. Conclusions Higher normalized atezolizumab dose was not associated with improved outcomes. Substantial clinical and tumor-type imbalances preclude causal, equivalence, or noninferiority conclusions. These findings support prospective randomized dose-optimization studies rather than routine dose modification.
Background Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are autoimmune disorders marked by the presence of pathogenic autoantibodies predominantly produced by B cells. Both conditions are chronic, incurable, and require lifelong treatment. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising treatment for refractory hematological malignancies, with anti-CD19 CAR-T therapy demonstrating high efficacy in relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The profound depletion of B cells induced by anti-CD19 CAR-T therapy suggests that this treatment may influence the clinical course of patients with DLBCL and concomitant SLE or APS. Materials and methods We report two clinical cases of patients diagnosed with both DLBCL and concomitant SLE and APS who underwent anti-CD19 CAR-T therapy at our institution. We describe the lymphoproliferative disease course as well as the serological evolution and longitudinal cytokine profiles measured before and after CAR-T therapy. Results In both cases, CAR-T therapy resulted in complete and long-lasting metabolic remission of the lymphoproliferative disorder. Concurrently, autoantibody titers stabilized, permitting stepwise de-escalation of the immunomodulatory treatment. Conclusion These cases demonstrate that CAR-T therapy for DLBCL is feasible and appears safe in patients with concomitant autoimmune disease but requires close monitoring and interdisciplinary management. These findings support further preclinical and clinical investigation of CAR-T therapy as a potential therapeutic approach in patients with DLBCL and concomitant SLE and APS.
Background:Germline BRCA1 (gBRCA1) pathogenic variants (PVs) are the most common cause of inherited breast cancer. Preclinical studies have shown that homozygous loss of BRCA1 in T cells impairs T cell-mediated antitumour immunity. However, the consequences of heterozygous gBRCA1 on human T cell function are unknown. Patients and methods:We collected peripheral blood mononuclear cells (PBMCs) from healthy donors and treatment-naïve patients diagnosed with early-stage breast cancer with or without a gBRCA1 PV. T cells derived from PBMC were activated in vitro and analysed for phenotypic and functional differences. To investigate the impact of gBRCA1 PV on tumour-infiltrating lymphocytes (TILs), we carried out T cell receptor (TCR) sequencing and whole exome sequencing on triple negative breast cancer (TNBC) tumours from gBRCA1 carriers and wild-type (WT) patients. Results:Patients with gBRCA1 PV had significantly reduced circulating T cell counts compared with WT individuals. BRCA1 protein was highly expressed in healthy donor activated T cells, but significantly reduced expression was observed in gBRCA1 patients compared with WT. Activated T cells from gBRCA1 carriers displayed a distinct transcriptional profile with significantly impaired proliferation and decreased effector molecule production. TCR sequencing of TILs extracted from TNBC tumours from gBRCA1 carriers revealed significantly more hyperexpanded T cell clones than in WT patients, with hyperexpansion correlating with increased tumour mutation burden (R 2 = 0.86), particularly frameshift mutations (R 2 = 0.72). Conclusions:Circulating T cells from gBRCA1 carriers exhibit intrinsic T cell dysfunction. This phenotype may be clinically relevant in the context of antitumour immunity, cancer development, progression and response to immunotherapy treatment.
Background Brown adipose tissue (BAT) activity has been suggested to play a role in cancer progression. Previous studies have shown that BAT activity is higher in patients with cancer, and that BAT volume is a predictor of tumour recurrence and mortality in patients with cancer, but the data on melanoma are limited. Patients and methods Here, we re-analysed 2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (FDG–PET–CT) images from 135 patients with cutaneous melanoma treated at Turku University Hospital between 2012 and 2021 to assess associations among BAT, melanoma progression, patient survival, and patient weight. We applied a three-stage universal BAT threshold definition using predetermined standardised uptake value thresholds of 0.8, 1.0, and 1.2 g/ml, given the retrospective nature of our study. Of the 135 patients (81 men and 54 women; median age 61 years, interquartile range 54-71), 40 (29.6%), 24 (17.8%), and 19 (14.1%) were BAT-positive at the 0.8, 1.0, and 1.2 g/ml thresholds, respectively. Results Our results showed that patients with active melanoma on FDG–PET–CT imaging were more frequently BAT-positive at the 0.8 threshold (P = 0.026) and 1.0 threshold (P = 0.016). We also found a significantly higher BAT volume among patients who survived the observation period (0.8, 1.0, and 1.2 g/ml thresholds; P = 0.018, P = 0.038, and P = 0.571, respectively) and those who did not relapse (0.8, 1.0, and 1.2 g/ml thresholds; P = 0.631, P = 0.012, and P = 0.030, respectively). Conclusions No association between BAT positivity and relapse-free survival or overall survival was observed at any threshold. Although higher BAT volumes were observed in subgroups of patients who survived or did not relapse, these findings were not supported by survival analyses and should be considered exploratory.
