Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy

Abstract

BackgroundAdoptive cell therapy with T cells genetically engineered to express a chimeric antigen receptor (CAR-T) or tumor-infiltrating T lymphocytes (TIL) demonstrates impressive clinical results in patients with cancer. Lymphodepleting preconditioning prior to cell infusion is an integral part of all adoptive T cell therapies. However, to date, there is no standardization and no data comparing different non-myeloablative (NMA) regimens.MethodsIn this study, we compared NMA therapies with different doses of cyclophosphamide or total body irradiation (TBI) in combination with fludarabine and evaluated bone marrow suppression and recovery, cytokine serum levels, clinical response and adverse events.ResultsWe demonstrate that a cumulative dose of 120 mg/kg cyclophosphamide and 125 mg/m2 fludarabine (120Cy/125Flu) and 60Cy/125Flu preconditioning were equally efficient in achieving deep lymphopenia and neutropenia in patients with metastatic melanoma, whereas absolute lymphocyte counts (ALCs) and absolute neutrophil counts were significantly higher following 200 cGyTBI/75Flu-induced NMA. Thrombocytopenia was most profound in 120Cy/125Flu patients. 30Cy/75Flu-induced preconditioning in patients with acute lymphoblastic leukemia resulted in a minor ALC decrease, had no impact on platelet counts and did not yield deep neutropenia. Following cell infusion, 120Cy/125Flu patients with objective tumor response had significantly higher ALC and significant lower inflammatory indexes, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Receiver-operating characteristics curve analysis 7 days after cell infusion was performed to determine the cut-offs, which distinguish between responding and non-responding patients in the 120Cy/125Flu cohort. NLR≤1.79 and PLR≤32.7 were associated with clinical response and overall survival. Cytokine serum levels did not associate with clinical response in patients with TIL. Patients in the 120Cy/125Flu cohort developed significantly more acute NMA-related adverse events, including thrombocytopenia, febrile neutropenia and cardiotoxicity, and stayed significantly longer in hospital compared with the 60Cy/125Flu and TBI/75Flu cohorts.ConclusionsBone marrow depletion and recovery were equally affected by 120Cy/125Flu and 60Cy/125Flu preconditioning; however, toxicity and consequently duration of hospitalization were significantly lower in the 60Cy/125Flu cohort. Patients in the 30Cy/75Flu and TBI/75Flu groups rarely developed NMA-induced adverse events; however, both regimens were not efficient in achieving deep bone marrow suppression. Among the regimens, 60Cy/125Flu preconditioning seems to achieve maximum effect with minimum toxicity.

Tumor Infiltrating Lymphocyte (TIL) Therapy for Solid Tumor Treatment: Progressions and Challenges

“…However, there was no obvious effect in a randomized trial [ 68 ]. Recently, a study summarized different NMA regimens, and suggested that the regimen of Cy (30 mg/kg for two days) and Flu (25 mg/m 2 for five days) is a better choice [ 69 ], which has maximum effect on lymphodepletion with minimum toxicity compared to other doses and regimens. Notably, most patients have experienced adverse effects caused by the NMA lymphodepletion regimen, such as neutropenia, lymphopenia, and coagulopathy, which are hematological side effects [ 5 , 70 ].…”

“…Notably, most patients have experienced adverse effects caused by the NMA lymphodepletion regimen, such as neutropenia, lymphopenia, and coagulopathy, which are hematological side effects [ 5 , 70 ]. Non-hematological events include nausea, headaches, loss of appetite, neutropenic fever, diarrhea, and hyperbilirubinemia [ 5 , 69 ], which are mostly manageable by standard supportive treatment. Interestingly, in order to avoid the severe toxicity of the NMA lymphodepletion regimen, Santos et al designed a regimen which used oncolytic adenoviruses to replace NMA lymphodepleting which resulted in great efficacy [ 71 ].…”

Peripheral blood persistence and expansion of transferred non-genetically modified Natural Killer cells might not be necessary for clinical activity

“…In agreement with both above-mentioned studies, Hirayama et al [ 40 ] recently showed that a favorable cytokine profile induced by lymphodepletion is associated with better clinical outcomes and tend to be obtained by higher dose lymphodepletion. On the other hand, there is no apparent difference in clinical activity between different regimens of low to moderate intensity [ 41 ].…”

Lymphodepleting chemotherapy practices and effect on safety and efficacy outcomes in patients with solid tumours undergoing T cell receptor-engineered T cell (TCR-T) Therapy: a systematic review and meta-analysis

“…Adoption of this LD regimen in CAR-T cell therapy demonstrated that higher dose cyclo/fludara use was also associated with improved efficacy [38][39][40] but an increased toxicity burden in both haematological and solid tumours [12]. Consequently, a range of lower cyclo/ fludara doses have been studied as LD in ACT therapy in solid tumours [12,[49][50][51]. For this review, we considered the original standard LD regimens containing total doses of cyclo ≥ 120 mg/kg and fludara ≥ 100 mg/m 2 as ''high dose''.…”