24 research outputs found
LUMINOS-102: Lerapolturev with and without α-PD- 1 in unresectable α-PD- 1 refractory melanoma
Lerapolturev (lera, formerly PVSRIPO) is a novel poliovirus based intratumoral immunotherapy that infects both cancer cells and antigen-presenting cells (APCs) via CD155, the poliovirus receptor. Lera has direct anticancer effects while also generating type I/III interferon-dominated inflammation and anti-tumor T-cell priming and activation via infection of local APCs. LUMINOS-102 (NCT04577807) is a multi-center, open-label, two-arm randomized Phase 2 study investigating the efficacy and safety of lera ± α-PD- 1 in patients with unresectable melanoma who failed prior α-PD- 1 therapy. Cross-over to the α-PD- 1 arm is permitted after progression, PR for ≥6 mo or 6 mo on treatment with SD. The maximum initial lera dose was 6x108 TCID50 /visit every 3 or 4 weeks (Q3/4 W). As of March 2022, the maximum lera dose was increased to 1.6 x 109 TCID50/visit, every week (QW) for 7 weeks (induction), followed by Q3/4 W dosing (maintenance). As of 20-Jun- 2022, 21 participants (10 male, 11 female, median 64 yrs) received lera (n = 14 at initial dose, Q3/4 W; n = 4 at increased dose, Q3/4 W; n = 3 at increased dose, QW) ± αPD-1. Five patients are currently on treatment. With the initial regimen, no objective responses and a CBR of 7% were observed. However, with the higher dose regimen, 1 complete response and a CBR of 71% (5/7) has been observed. Two of 4 participants with stable disease have evidence of response (1 with resolution of uninjected lung metastasis, 1 with decreased PET signal in injected and uninjected lesions receiving combination therapy). The only treatment related AE in \u3e1 pt was fatigue (19%, all grade 1 or 2). No dose-limiting toxicities or treatment-related SAEs were reported. Multiplex-IF analysis of on-treatment tumor biopsies will be presented. Lera ± αPD-1 is well tolerated, with early signs of efficacy at the higher dose level. Enrollment and randomization are ongoing
Mucosal inflammation predicts response to systemic steroids in immune checkpoint inhibitor colitis
Background Immune-related colitis is a common, often serious complication of immune checkpoint inhibition (ICI). Although endoscopy is not strictly recommended for any grade of diarrhea/colitis, emerging evidence suggests that endoscopic evaluation may have important therapeutic implications. In this retrospective study, we sought to comprehensively characterize the clinical and histologic features of ICI-induced colitis with a specific focus on evaluating the prognostic role of endoscopy.Methods Data were collected from the medical records of 130 patients with confirmed ICI-induced colitis. In a subset of patients (n=44) with endoscopic and pathologic data, endoscopic data were scored using the Mayo Endoscopic Score (MES) with scores ranging from 0 (no inflammation) to 3 (colonic ulceration). The impact of infliximab on antitumor outcomes was evaluated using progression-free survival (PFS) and overall survival (OS).Results We identified 130 patients with ICI-induced colitis across two institutions. All patients were treated with corticosteroids. Additional and/or alternative immunosuppression was employed in 59 cases, with 52 patients (42%) requiring at least one infusion of infliximab 5 mg/kg. Endoscopic assessment with biopsy was performed in 123 cases of suspected colitis (95%), with 44 cases available for MES tabulation. Presence of ulceration (MES 3) was associated with use of infliximab (p=0.008) and MES was significantly higher in patients who received infliximab compared with those who did not (p=0.003) with a median score of 2.5; conversely, those with an MES of zero rarely required secondary immunosuppression. Notably, symptoms of colitis based on Common Terminology Criteria for Adverse Events grade had no association with endoscopic findings based on MES classification. After adjustment for baseline patient and disease characteristics, there was no significant difference in steroid duration or cancer-related outcomes in patients treated with infliximab.Conclusions In our study, we demonstrate the association of endoscopic features, specifically the MES, with immunosuppressive needs. Importantly, we also show that MES was not related to severity of patient symptoms. The data suggest that endoscopic features can guide clinical decision-making better than patient symptoms, both identifying high-risk patients who will require infliximab and those who are likely to respond to initial corticosteroids
Immune checkpoint inhibitor-associated celiac disease
Background Rare cases of immune checkpoint inhibitor (ICI)-associated celiac disease (ICI-CeD) have been reported, suggesting that disruption of tolerance mechanisms by ICIs can unmask celiac disease (CeD). This study aims to characterize the clinicopathological and immunophenotypic features of ICI-CeD in comparison to ICI-associated duodenitis (ICI-Duo) and usual CeD.Methods A medical and pathological records search between 2015 and 2019 identified eight cases of ICI-CeD, confirmed by tTG-IgA. Nine cases of ICI-Duo, 28 cases of moderate CeD, as well as 5 normal controls were used as comparison groups. Clinical information was collected from the electronic medical records. Immunohistochemistry for CD3, CD8, T-cell receptor gamma/delta (γδ), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) were performed, with quantification of intraepithelial lymphocyte (IEL) subsets in three well-oriented villi. CD68, PD-L1, and PD-1 were assessed as a percentage of lamina propria surface area infiltrated by positive cells. Statistical significance was calculated by the Student’s t-test and Fisher’s exact test.Results The eight patients with ICI-CeD (F:M=1:3) and nine patients with ICI-Duo (F:M=5:4) presented similarly with diarrhea (13/17) and abdominal pain (11/17) after a median of 1.6 months on ICI therapy. In patients with ICI-CeD, tTG-IgA ranged from 104 to >300 IU/mL. Histological findings in ICI-CeD and ICI-Duo were similar and included expansion of the lamina propria, active neutrophilic duodenitis, variably increased IELs, and villous blunting. Immunohistochemistry showed that the average number of IELs per 100 enterocytes is comparable between ICI-CeD and ICI-Duo, with increased CD3+ CD8+ T cells compared with normal duodenum but decreased γδ T cells compared with CeD. Average PD-L1 percentage was 9% in ICI-CeD and 18% in ICI-Duo, in comparison to <1% in CeD and normal duodenum; average PD-1 percentage was very low to absent in all cases (<3%). On follow-up, five patients with ICI-CeD improved on a gluten-free diet (GFD) as the sole therapeutic intervention (with down-trending tTG-IgA) while the other three required immunosuppression. All patients who developed ICI-Duo received immunosuppression with variable improvement in symptoms.Conclusions ICI-CeD resembles ICI-Duo clinically and histologically but shares the serological features and response to gluten withdrawal with classic CeD. Immunophenotyping of IELs in ICI-CeD and ICI-Duo also shows similar CD3, CD8, γδ T cell subsets, and PD-L1 populations, all of which differed quantitatively from usual CeD. We conclude that ICI-CeD is biologically similar to ICI-Duo and is likely a variant of ICI-Duo, but treatment strategies differ, with ICI-CeD often improving with GFD alone, whereas ICI-Duo requires systemic immunosuppression
Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy
Immune checkpoint inhibitors have emerged as a revolutionary treatment option for patients with various types of malignancy. Although these agents afford a significant improvement in outcomes for melanoma and other previously untreatable malignancies, their novel mechanism of action may predispose patients to immune‐related adverse effects (irAEs). In the tumour neoantigen environment, these irAEs are due to the activation of the immune system by the blockade of suppressive checkpoints, leading to increases in T‐cell activation and proliferation. IrAEs have been reported in almost any organ and at any point in time, even months to years after discontinuation of therapy. Certain populations with distinct physiological changes, genetic risk factors, and specific antigen exposures may be more highly predisposed to develop irAEs. This review discusses the incidence and mechanisms of irAEs and the relationship between host factors and irAE occurrence