A phase I trial of infusing anti-CD3 × anti-CD20 bispecific antibody (CD20Bi) armed activated T cells (aATC) was conducted in high-risk/refractory non-Hodgkin’s lymphoma patients to determine whether aATC infusions are safe, affect immune recovery, and induce an antilymphoma effect. Ex vivo expanded ATC from 12 patients were armed with anti-CD20 bispecific antibody, cryopreserved, and infused after autologous stem cell transplantation (SCT). Patients underwent SCT after high-dose chemotherapy, and aATC infusions were started on day +4. The patients received 1 infusion of aATC per week for 4 weeks after SCT with doses of 5,10,15, and 20 × 109. aATC infusions were safe and did not impair engraftment. The major side effects were chills, fever, hypotension, and fatigue. The mean number of IFN-γ Enzyme-linked Immunosorbent Spots (ElSpots) directed at CD20 positive lymphoma cells (DAUDI, P = .0098) and natural killer cell targets (K562, P < .0051) and the mean specific cytotoxicity directed at DAUDI (P = .037) and K562 (P = .002) from pre-SCT to post-SCT were significantly higher. The increase in IFN-γ EliSpots from pre-SCT to post-SCT in patients who received armed ATC after SCT were significantly higher than those in patients who received SCT alone (P = .02). Serum IL-7, IL-15, Macrophage inflammatory protein (MIP)-1 beta, IP-10, MIP-1α, and Monokine induced by gamma interferone increased within hours after infusion. Polyclonal and specific antibodies were near normal 3 months after SCT. aATC infusions were safe and increased innate and specific antilymphoma cell immunity without impairing antibody recovery after SCT.
A pilot phase I clinical trial involving 15 infusions of anti-CD3 × anti-CD20 bispecific Ab (CD20Bi)-armed anti-CD3-activated T cells (aATC) and low-dose IL-2 was conducted in three non-Hodgkin’s lymphoma (NHL) patients (two high-risk and one refractory) after autologous SCT. The feasibility of T-cell expansion, safety of aATC infusions, cytotoxic immune responses and trafficking of aATC were evaluated. Three NHL patients received 15 infusions of 5 × 109 aATC (three infusions/week for 3 weeks and one infusion/week for 6 weeks) between days 1 and 65 after SCT with IL-2. There were no dose-limiting toxicities. Chills, fever, hypotension and malaise were the common side effects. Engraftment was delayed in one patient with a low stem cell dose. CD20Bi aATC infusions induced specific cytotoxicity directed at lymphoma targets. Endogenous peripheral blood mononuclear cells from two patients mediated anti-lymphoma cytotoxicity above preSCT background (P <0.001). 111In labeled aATC trafficked to the lungs at 1 h and accumulated in the liver and bone marrow after 24 h. aATC infusions given over 69 days in combination with IL-2 were safe, did not inhibit engraftment, and induced endogenous cytotoxic responses directed at lymphoma targets.
1914 Novel therapeutic approaches are needed for women with metastatic breast cancer (BrCa). In our phase I clinical trial, infusions of anti-CD3 activated T cells (ATC) armed with anti-CD3 x anti-Her2/neu bispecific antibody (Her2Bi) induced specific cytotoxicity (SC) directed at SK-BR-3 breast cancer cells by fresh peripheral blood lymphocytes (PBL) and induced elevated serum levels of Th1 cytokines. In this study, we took advantage of armed ATC induced anti-tumor immune responses by infusing “immune” T cells collected by leukopheresis. We expanded “immune T cells” with anti-CD3 and IL-2, followed by a cryopreservation for multiple re-infusions of ATC after high dose chemotherapy (HDC) and autologous stem cell transplant (SCT). We asked whether this approach would transfer anti-tumor responses back into patients after HDC and SCT to accelerate the development of cellular and humoral anti-tumor responses. This strategy of “prime” with armed ATC and “boost” with ATC was performed in 5 evaluable patients. The “priming” portion involved 8 infusions of (2 infusions/week for 4 weeks) armed ATC given with daily low dose IL-2 (300,000 IU/m2/day) and twice weekly GM-CSF (250 μg/m2). Approximately 3 weeks after the armed ATC infusions, patients underwent a second leukopheresis for the collection and expansion of ATC. The expanded ATC from 6 patients at an effector:target ratio (E/T) of 25:1 exhibited specific cytotoxicity (SC) ranging from 3.7–25.8 (mean = 13.6%) directed at the SK-BR-3. Phenotyping of the ATC showed a mean of 50.2 % (25–74) CD4+ cells, 30.4 % (16.3-51.3) CD8+ cells, 11.6% (4.5-24.3) CD56+CD16+ cells, and 29.5% (10.4–41) CD4+CD25+ cells. A separate leukopheresis after G-CSF stimulation was performed to obtain CD34+ cells for the SCT. After HDC and PBSCT, 5 evaluable patients received multiple infusions with a mean total of 54×109 ATC (16–110 × 109) beginning day +1 after SCT. No G-CSF was given to accelerate engraftment. There were no dose-limiting side effects or delays in engraftment. One patient developed sepsis, multiple organ failure and recovered fully with supportive care and antibiotics. Phenotyping at 2 weeks after SCT showed the mean proportions of CD4+ and CD8+ cells to be 55.5 and 17.7%, respectively. Specific cytotoxicity (SC) directed at SK-BR-3 targets ranged from 4.7 to 70% at E/T of 25:1 up to 18 months post SCT but not against a negative control cell line-Daudi. Mean serum anti-SK-BR-3 antibody levels were 800 ng/ml preSCT and 1500, 1080 and 1360 ng/ml at 1, 2, and 3 months post SCT, respectively. In vitro anti-SK-BR-3 antibody synthesis was assessed using a new assay (Thakur et al, Cancer Immunol Immunother EPub, 2011) showed easily detectable levels of in vitro anti-SK-BR-3 antibody synthesis. The mean anti-SK-BR-3 antibody synthesis in the presence of CpG in pre-immunotherapy (Pre-IT), mid-IT, 1 months post-IT, pre-SCT and 1, 2, and 3 months post-SCT is summarized in the table. PBL produced anti-SK-BR-3 antibody pre-SCT and there was clear recovery of anti-SK-BR-3 antibody synthesis by PBL at 2 and 3 months after SCT. These data show infusions of immune ATC transferred cytotoxic T lymphocytes and humoral antibody activity directed at tumor antigens. These novel findings suggest that adaptive immunity was transferred into patients by ATC infusions and the stem cell product after myeloablation and SCT leading to rapid reconstitution of anti-tumor immunity.Time PointsCulture ConditionsMean±SD (n=3)Pre-ITCpG23±27Mid-ITCpG66±671M Post-ITCpG41±67Pre-SCTCpG92±101M Post-SCTCpG9±182M Post-SCTCpG45±273M Post-SCTCpG82±55 Disclosures: Lum: Transtarget Inc: Equity Ownership, Founder of Transtarget.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.