Antibody-drug conjugates (ADCs) are a recent, revolutionary approach for malignancies treatment, designed to provide superior efficacy and specific targeting of tumor cells, compared to systemic cytotoxic chemotherapy. Their structure combines highly potent anti-cancer drugs (payloads or warheads) and monoclonal antibodies (Abs), specific for a tumor-associated antigen, via a chemical linker. Because the sensitive targeting capabilities of monoclonal Abs allow the direct delivery of cytotoxic payloads to tumor cells, these agents leave healthy cells unharmed, reducing toxicity. Different ADCs have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of a wide range of malignant conditions, both as monotherapy and in combination with chemotherapy, including for lymphoma patients. Over 100 ADCs are under preclinical and clinical investigation worldwide. This paper provides an overview of approved and promising ADCs in clinical development for the treatment of lymphoma. Each component of the ADC design, their mechanism of action, and the highlights of their clinical development progress are discussed.

While more than half of non-Hodgkin lymphomas (NHL) can be cured with modern frontline chemoimmunotherapy regimens, outcomes of relapsed and/or refractory (r/r) disease in subsequent lines remain poor, particularly if considered ineligible for hematopoietic stem cell transplantation. Hence, r/r NHLs represent a population with a high unmet medical need. This therapeutic gap has been partially filled by adoptive immunotherapy. CD19-directed autologous chimeric antigen receptor (auto-CAR) T cells have been transformative in the treatment of patients with r/r B cell malignancies. Remarkable response rates and prolonged remissions have been achieved in this setting, leading to regulatory approval from the U.S. Food and Drug Administration (FDA) of four CAR T cell products between 2017 and 2021. This unprecedented success has created considerable enthusiasm worldwide, and autologous CAR T cells are now being moved into earlier lines of therapy in large B cell lymphoma. Herein, we summarize the current practice and the latest progress of CD19 auto-CAR T cell therapy and the management of specific toxicities and discuss the place of allogeneic CAR T development in this setting.

Introduction: Intraperitoneal dissemination is a major problem resulting in very poor prognosis and a rapid marked deterioration in the quality of life of patients. Pressurised intraperitoneal aerosol chemotherapy (PIPAC) is an emergent laparoscopic procedure aiming to maximise local efficacy and to reduce systemic side effects. Methods and analysis: Nab-PIPAC, a bicentre open-label phase IB, aims to evaluate safety of nab-paclitaxel and cisplatin association using in patients with peritoneal carcinomatosis (PC) of gastric, pancreatic or ovarian origin as ≥1 prior line of systemic therapy. Using a 3+3 design, sequential intraperitoneal laparoscopic application of nab-paclitaxel (7.5, 15, 25, 37.5, 52.5 and 70 mg/m ² ) and cisplatin (10.5 mg/m ² ) through a nebuliser to a high-pressure injector at ambient temperature with a maximal upstream pressure of 300 psi. Treatment maintained for 30 min at a pressure of 12 mm Hg and repeated4–6 weeks intervals for three courses total. A total of 6–36 patients are expected, accrual is ongoing. Results are expected in 2024. The primary objective of Nab-PIPAC trial is to assess tolerability and safety of nab-paclitaxel and cisplatin combination administered intraperitoneally by PIPAC in patients with PC of gastric, pancreatic or ovarian origin. This study will determine maximum tolerated dose and provide pharmacokinetic data. Ethic and dissemination: Ethical approval was obtained from the ethical committees of Geneva and Vaud (CCER-2018-01327). The study findings will be published in an open-access, peer-reviewed journal and presented at relevant conferences and research meetings. Trial registration number: NCT04000906 .

Immune checkpoint blockade (ICB) has revolutionized the prognosis of several advanced-stage solid tumors. However, its success has been far more limited in hematological malignancies and is mostly restricted to classical Hodgkin lymphoma (cHL) and primary mediastinal B cell lymphoma (PMBCL). In patients with non-Hodgkin lymphoma (NHL), response to PD-1/PD-L1 ICB monotherapy has been relatively limited, although some subtypes are more sensitive than others. Numerous predictive biomarkers have been investigated in solid malignancies, such as PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability (MSI), among others. This review aims to appraise the current knowledge on PD-1/PD-L1 ICB efficacy in lymphoma when used either as monotherapy or combined with other agents, and describes potential biomarkers of response in this specific setting.

There are limited data regarding the combined value of the pretransplant Deauville score (DS) from a positron emission tomography scan and clinical risk factors in patients with relapsed/refractory aggressive non-Hodgkin lymphoma (NHL). We performed a retrospective analysis to assess the prognostic role of pretransplant DS in patients with relapsed/refractory aggressive NHL who underwent salvage chemotherapy and autologous stem cell transplantation (ASCT). We identified 174 eligible patients between January 2013 and March 2019. In multivariable analysis, pretransplant DS, B symptoms, and secondary International Prognostic Index (sIPI) were independent risk factors for event-free survival (EFS). These variables were used to derive an integrated risk score that categorized 166 patients with available information for all risk factors into 3 groups: low (n = 92; 55.4%), intermediate (n = 48; 28.9%), and high (n = 26; 15.7%). The new prognostic index showed a strong association with EFS (low-risk vs intermediate-risk hazard ratio [HR], 3.94; 95% confidence interval [CI], 2.16-7.17; P < .001; low-risk vs high-risk HR, 10.83; 95% CI, 5.81-20.19; P < .001) and outperformed models based on clinical risk factors or DS alone. These results were validated in 60 patients from an independent external cohort (low-risk vs intermediate-risk HR, 4.04; 95% CI, 1.51-10.82; P = .005; low-risk vs high-risk HR, 10.49; 95% CI, 4.11-26.73; P < .001). We propose and validate a new prognostic index that risk-stratifies patients undergoing salvage chemotherapy followed by ASCT, thereby identifying patients at high risk for posttransplant treatment failure.

Immune checkpoint blockade (ICB) has indeed transformed the outlook for many advanced-stage solid tumors, yet its effectiveness in hematological malignancies has been particularly limited, with success predominantly demonstrated in classical Hodgkin lymphoma (cHL) and immune-privilege subtypes of non-Hodgkin lymphoma (NHL). In this report, we present an impactful case of a 71-year-old man grappling with refractory follicular lymphoma (rFL) that had progressed to a high-grade lymphoma, leaving no conventional treatment options on the table. Notably, the histological examination of the tumor tissue revealed a markedly elevated PD-L1 expression, illuminating the potential for immunotherapy to be effective. Additionally, comprehensive gene sequencing unveiled a moderate tumor mutational burden (TMB), deepening our understanding of the tumor’s molecular intricacies. As his health declined with no access to cell therapies or clinical trials at that time, a combination treatment of PD-1 ICB and an anti-CD20 drug surprisingly led to a significant improvement in his condition and long-term remission. While PD-1 ICB therapy has historically shown limited responses in non-Hodgkin lymphomas (NHLs), this case serves as a beacon of optimism, underscoring the promise of combining immunotherapy modalities and the potential of comprehensive molecular assessments in charting innovative treatments for extensively treated NHL patients. The quest for predictive biomarkers to gauge treatment response remains a formidable challenge. This report serves as a testament to the ever-evolving landscape of cancer treatment, where precision medicine and immunotherapy continue to unlock new possibilities for those confronting the most challenging malignancies.