scholarly journals Immune and Inflammatory Cells of the Tumor Microenvironment Represent Novel Therapeutic Targets in Classical Hodgkin Lymphoma

2019 ◽  
Vol 20 (21) ◽  
pp. 5503 ◽  
Author(s):  
Eleonora Calabretta ◽  
Francesco d’Amore ◽  
Carmelo Carlo-Stella
Keyword(s):  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
Suppressor Cells ◽  
Inflammatory Cells ◽  
Brentuximab Vedotin ◽  
New Drugs ◽  
Classical Hodgkin Lymphoma ◽  
Relevant Role

Classical Hodgkin Lymphoma (cHL) is a B-cell malignancy that, typically, responds well to standard therapies. However, patients who relapse after standard regimens or are refractory to induction therapy have a dismal outcome. The implementation of novel therapies such as the anti-CD30 monoclonal antibody Brentuximab Vedotin and immune checkpoint inhibitors has provided curative options for many of these patients. Nonetheless, responses are rarely durable, emphasizing the need for new agents. cHL is characterized by a unique microenvironment in which cellular and humoral components interact to promote tumor survival and dissemination. Knowledge of the complex composition of cHL microenvironment is constantly evolving; in particular, there is growing interest in certain cell subsets such as tumor-associated macrophages, myeloid-derived suppressor cells and neutrophils, all of which have a relevant role in the pathogenesis of the disease. The unique biology of the cHL microenvironment has provided opportunities to develop new drugs, many of which are currently being tested in preclinical and clinical settings. In this review, we will summarize novel insights in the crosstalk between tumor cells and non-malignant inflammatory cells. In addition, we will discuss the relevance of tumor-microenvironment interactions as potential therapeutic targets.

scholarly journals Immune checkpoint inhibitors in combination with radiotherapy as salvage treatment for relapsed/refractory classical Hodgkin lymphoma: A retrospective analysis in 12 patients

2021 ◽  
Vol 13 (2) ◽  
Author(s):  
Elisa Lucchini ◽  
Chiara Rusconi ◽  
Mario Levis ◽  
Francesca Ricci ◽  
Armando Santoro ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Median Number ◽  
Brentuximab Vedotin ◽  
Salvage Treatment ◽  
Classical Hodgkin Lymphoma ◽  
Highly Active

The rate of complete remission (CR) with the anti-PD1 immune checkpoint inhibitors (ICI) nivolumab (N) and pembrolizumab (P) in patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) is low (20-30%), and the majority of patients eventually relapse. One strategy to improve their outcome is to combine ICI with radiotherapy (ICI-RT), taking advantage of a supposed synergistic effect. We retrospectively collected data of 12 adult patients with R/R cHL treated with ICI-RT delivered during or within 8 weeks from the start or after the end of ICI. Median age at ICI-RT was 37 years, 50% had previously received an autologous stem cell transplantation (SCT) and 92% brentuximab vedotin. RT was given concurrently, before or after ICI in 4, 1 and 7 patients. Median RT dose was 30Gy, for a median duration of 22 days. Median number of ICI administrations was 15. Overall response and CR rate were 100% and 58%. Nine patients received subsequent SCT consolidation (7 allogeneic and 2 autologous). After a median follow-up of 18 months, 92% of patients were in CR. No major concerns about safety were reported. ICI-RT combination appears to be a feasible and highly active bridge treatment to transplant consolidation.

Treatment of classical Hodgkin lymphoma in the era of brentuximab vedotin and immune checkpoint inhibitors

2018 ◽  
Vol 97 (8) ◽  
pp. 1301-1315 ◽  
Author(s):  
A. M. Carella ◽  
P. Corradini ◽  
A. Mussetti ◽  
U. Ricardi ◽  
U. Vitolo ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Brentuximab Vedotin ◽  
Classical Hodgkin Lymphoma

scholarly journals Low-Dose Nivolumab Plus Brentuximab Vedotin As a Bridge to Stem Cell Transplantation in Relapsed/Refractory Classical Hodgkin Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4534-4534
Author(s):  
Perla R. R. Colunga-Pedraza ◽  
Edgar Ulises Coronado-Alejandro ◽  
Fernando De La Garza ◽  
Eliezer Tomas Gomez Gomez ◽  
Andres Gomez-De Leon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Hodgkin Lymphoma ◽  
Low Dose ◽  
Progression Free Survival ◽  
Brentuximab Vedotin ◽  
New Drugs ◽  
Fixed Dose ◽  
Classical Hodgkin Lymphoma ◽  
Median Dose ◽  
Low Middle Income Countries

Abstract Background: Up to one-third of patients with Hodgkin lymphoma (HL) are not responsive to first-line therapy or eventually relapse. New drugs, including anti-PDL1 (i.e., nivolumab) and monoclonal antibodies (i.e., brentuximab vedotin (BV)), have changed the landscape in the treatment of HL. However, the financial toxicity associated with these new drugs is worrisome and are practically inaccessible to most patients living in low-middle income countries. The approved dose of nivolumab in refractory classical Hodgkin Lymphoma (HL) is 3 mg/kg, but lower doses have demonstrated efficacy. Objective: To assess the efficacy of low-dose nivolumab at a fixed dose of 40 mg, 100 mg, or 140 mg in combination with BV 1.8 mg/kg every three weeks in patients with relapsed or refractory (R/R) HL. Methods: We conducted a retrospective analysis of adults with R/R HL who received BV at 1.8 mg/kg and low-dose nivolumab at a fixed dose of 40 mg, 100 mg, or 140 mg IV every three weeks. Patients were routinely offered the highest dose possible that could be afforded for at least 4 cycles, as treatment costs were covered out of pocket. We calculated treatment responses, and overall survival (OS), and progression-free survival (PFS) with the Kaplan-Meier method. Results: A total of 10 patients (50% male, median of age 26.5 years (15-50)) with R/R HL were included; n=7 relapsed and n=3 refractory patients. Median follow-up was 11.5 months (range, 5-18) (antes o después del BV/nivo?). The median previous lines of treatment were three (range, 1-4) and regimens were ESHAP (2, 20%), IGEV (3, 30%)), CGEV (1, 10%), ICE (3, 30%), and allogenic transplantation (1, 10%). Six patients (60%) had received radiotherapy (median dose: 21.5 Gy, range: 20-25). Five patients (50%) received 40 mg of nivolumab, n=3 100 mg (30%) and n=2 140mg (20%). The median dose per cycle was 0.93 mg/kg (range, 0.48-1.9 mg/kg). After a median of 4 (range, 4-8) cycles of low-dose nivolumab + BV the overall response rate was 80% (n=8); five obtained a complete response (CR) (50%) and n=3 a partial response (30%) . One patient (10%) had stable disease, and the other progressed (10%). Grade 1 or 2 adverse events occurred in n=6 patients (60%), including neuropathy (n=2), grade 1 leucopenia (n=3), fever (n=1), and myalgia (n=1). No grade III or IV adverse events were reported. One-year OS and PFS was 83.3%. Transplant consolidation was conducted in six cases (60%) (three autologous and three haploidentical), three are awaiting transplantation and one relapsed after achieving CR before transplant conditioning. One patient died on day +21 after haploidentical transplantation in the context of progressive disease. Conclusion: A short course of low-dose nivolumab and BV showed remarkable efficacy, achieving response in most patients with minimal toxicity and allowed patients with R/R HL who could not afford standard doses to undergo transplantation. The real-world safety and efficacy of low-dose nivolumab and BV should be further addressed in more extensive prospective studies. Figure 1 Figure 1. Disclosures Gomez-De Leon: ASH: Research Funding; Sanofi: Honoraria; Novartis: Honoraria; Abbvie: Honoraria. Gomez-Almaguer: Janssen: Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau.

scholarly journals Patients with classical Hodgkin lymphoma experiencing disease progression after treatment with brentuximab vedotin have poor outcomes

2016 ◽  
Vol 27 (7) ◽  
pp. 1317-1323 ◽  
Author(s):  
C.Y. Cheah ◽  
D. Chihara ◽  
S. Horowitz ◽  
A. Sevin ◽  
Y. Oki ◽  
...  
Keyword(s):  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Brentuximab Vedotin ◽  
Classical Hodgkin Lymphoma ◽  
Poor Outcomes

scholarly journals Tumor Microenvironment in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma before and after Anti-PD-1 Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Artem A. Gusak ◽  
Kirill V. Lepik ◽  
Natalia B. Mikhailova ◽  
Elena Kondakova ◽  
Yuri R. Zalaylov ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Observational Studies ◽  
Principal Investigator ◽  
Immune Checkpoints ◽  
Rank Test ◽  
Classical Hodgkin Lymphoma ◽  
Significance Level ◽  
Cell Counts ◽  
Before And After

Background.Tumor tissue in classical Hodgkin Lymphoma (cHL) contains 1-10% malignant Hodgkin/Reed-Sternberg cells and a significant number of immune cells in the tumor microenvironment that are characterized by expression of inhibitory molecules (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT). Despite overall effectiveness of anti-PD-1 treatment many patients still have relapsed or refractory (r/r) disease, therefore the search for predictive/prognostic biomarkers in patients on immunotherapy is highly demanded. Materials and methods.The study included 39 primary tumor specimens from patients with r/r cHL obtained before starting the treatment with nivolumab (primary biopsies). Specimens from 11 patients were studied before and after treatment (sequential biopsies). Treatment response was evaluated by PET-CT according to LYRIC criteria. Immunohistochemical staining for CD68, CD163, PD-1, LAG-3, TIM-3, CTLA-4, TIGIT was performed with an automated staining system (Bond III; Leica Biosystems). The slides were scanned with Aperio ScanScope XT (AperioTechnologies Inc.) and were analyzed with ImageScope Analysis software (Aperio Technologies) и Qupath (https://qupath.github.io). We explored progression-free survival (PFS) depending on the proportion of cells positive for CD68, CD163, PD-1, LAG-3, TIM-3, CTLA-4, TIGIT in the tumor microenvironment and analyzed the changes of these parameters between primary and sequential biopsies after treatment with nivolumab. Statistical analysis was performed using SPSS software (v.23). Data on sequential biopsies were analyzed with the Wilcoxon signed-rank test. PFS was calculated with the Kaplan-Meier method. The significance level was p ≤ 0.05. Results.A significant correlation was found in primary biopsies group between the value of CD163 and CTLA-4 (correlation coefficient -0,62, p < 0.05). There was no significant association between PFS and proportion of cells positive for CD68, PD-1, TIM-3, CTLA-4, TIGIT, LAG-3 in primary biopsies group. ROC analysis allowed to establish a 9% cut-off value of CD163 expression, dividing these patients into subgroups of CD163high and CD163low. In the CD163low group, the two-year PFS was 19,1% (95% CI 6%-37,7%) with a median PFS of 8,8 months (95% CI 5,7-12) and in the CD163high group - 53,8% (95% CI 28,4%-73,7%) with a median of 24,8 months (95% CI 18,8 - 39,2). In sequential biopsies, a statistically significant increase in numbers of PD-1+ and TIGIT+ T-cells and depletion of CD68+ and CD163+ cells was observed compared to corresponding cell counts in primary biopsies (median PD-1 - 3% vs 10%; median TIGIT - 10% vs 14%; median CD68 - 10% vs 7%; median CD163- 8% vs 3,5%; р <0,05). Conclusion.A comprehensive analysis of expression of CD68, CD163, LAG-3, TIGIT, CTLA4, TIM-3, PD-1 was performed in patients with r/r cHL before and after treatment with nivolumab. Significant association was found between the expression of CD163 and CTLA4. The results of the study indicate inferior PFS among patients with low expression (<9%) of CD163 in lymph node samples before immunotherapy. Biopsies taken after treatment with nivolumab showed a statistically significant increase in the number of PD-1+ and TIGIT+ cells and a decrease in the number of CD68+ and CD163+ cells compared with data from primary biopsies. The results of the study may contribute to our knowledge regarding biology of classical Hodgkin lymphoma and the mechanisms of resistance to therapy with immune checkpoints inhibitors. This study was supported by BMS research grant CA209-8EG Disclosures Ionova: Takeda:Other: principal investigator of the observational studies sponsored by Takeda;BMS:Other: principal investigator of the observational studies sponsored by BMS.

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