Maintenance therapy with ex vivo expanded lymphokine‐activated killer cells and rituximab in patients with follicular lymphoma is safe and may delay disease progression

Abstract

Summary Anti‐cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) have shown promise in follicular lymphoma (FL) as post‐induction therapy, by enhancing antibody‐dependent cellular cytotoxicity (ADCC). However, cytotoxic cells are reduced after this treatment. We hypothesised that ex vivo expanded lymphokine‐activated killer (LAK) cells administered to FL‐remission patients are safe and improve anti‐CD20 efficacy. This open, prospective, phase II, single‐arm study assessed safety and efficacy of ex vivo expanded LAK cells in 20 FL‐remission patients following rituximab maintenance. Mononuclear cells were obtained in odd rituximab cycles and stimulated with interleukin 2 (IL‐2) for 8 weeks, after which >5 × 108 LAK cells were injected. Patients were followed‐up for 5 years. At the end of maintenance, peripheral blood cells phenotype had not changed markedly. Natural killer, LAK and ADCC activities of mononuclear cells increased significantly after recombinant human IL‐2 (rhIL‐2) stimulation in all cycles. Rituximab significantly enhanced cytotoxic activity. No patients discontinued treatment. There were no treatment‐related serious adverse events. Three patients had progressed by the end of follow‐up. After a median (interquartile range) follow‐up of 59.4 (43.8–70.9) months, 85% of patients remained progression free. No deaths occurred. Quality‐of‐life improved throughout the study. Post‐induction LAK cells with rituximab seem safe in the long term. Larger studies are warranted to confirm efficacy.

The Future of Natural Killer Cell Immunotherapy for B Cell Non-Hodgkin Lymphoma (B Cell NHL)

“…Antibody-based therapy has become a critical part of the treatment landscape in hematologic malignancies in the past few decades and several monoclonal In patients with DLBCL and follicular lymphoma treated with anti-CD20 monoclonal antibodies, low pre-treatment NK cell count was associated with shorter progression free survival and decreased overall survival compared to patients with higher pre-treatment NK cells [45]. NK cell ADCC has been exploited in antibody therapy by systemic cytokine stimulation of endogenous NK cells [46][47][48][49][50] or in combination with adoptive NK cell therapy [43,51]. Autologous cytokine-expanded NK cells were combined with chemotherapy and rituximab in 9 patients with relapsed CD20positive lymphoma patients to enhance ADCC [43].…”

Long-term survival of a feline with non-T/B large granular lymphocyte lymphoma treated with chemotherapy and activated lymphocyte therapy

“…Based on the findings of these studies, concurrent treatment with chemotherapy and activated lymphocyte therapy could be preferred to activated lymphocyte therapy alone; however further controlled studies are required to clarify the efficacy of activated lymphocyte therapy for feline LGLL. Moreover, the potential toxicity and safety issues of the activated lymphocyte therapy make the use of this therapy controversial, although some reports have described that this therapy is safe in cats and other species ( Takayama et al ., 2000 ; Hoshino et al ., 2008 ; O’Connor et al ., 2012 ; Maeta et al ., 2019 ; López-Díaz de Cerio et al ., 2020 ; Gareau et al ., 2021 ; Mitani et al ., 2021 ). In a human randomized trial, compared with surgical resection alone, activated lymphocyte therapy after surgical resection of hepatocellular carcinoma decreased the frequency of recurrence, prolonged the time to first recurrence, improved the recurrence-free survival, and improved the disease-specific survival ( Takayama et al ., 2000 ).…”

“…This therapy is generally administered in combination with chemotherapy in veterinary medicine ( O’Connor and Wilson-Robles, 2014 ; Bujak et al ., 2018 ). In human and canine cancer patients, concurrent treatment with activated lymphocyte therapy and chemotherapy decreased recurrence risk, improved the quality of life (QOL), or prolonged survival time without serious adverse events ( Takayama et al ., 2000 ; O’Connor et al ., 2012 , 2013 ; López-Díaz de Cerio et al ., 2020 ; Mitani et al ., 2021 ). Furthermore, activated lymphocyte therapy was reported to be safe and feasible for postoperative QOL maintenance in older feline cancer patients ( Maeta et al ., 2019 ).…”

Oxidized-Desialylated Low-Density Lipoprotein Inhibits the Antitumor Functions of Lymphokine Activated Killer Cells

“…Among the immunotherapy methods being considered for anticancer therapy, adoptive transfer of lymphokine-activated killer (LAK) cells is one of the biotherapy approaches that has been translated into clinical studies [1][2][3][4][5]. In vitro culture of peripheral blood mononuclear cells (PBMCs) with interleukin-2 (IL-2) for several days results in a population of LAK cells with upregulated cytotoxicity against cancer cells and IFN-γ production [6].…”

“…Several clinical trials have successfully activated and expanded LAK cells using IL-2 [1,2,7,[10][11][12]. When LAK cells were first introduced by Rosenberg et al in 1985 [10,11], eleven of 25 patients showed significant cancer reduction, with one showing complete tumor regression.…”