Allogeneic Stem Cell Immunotherapy for Advanced Metastatic Breast Cancer: Lessons from Experience
Authors: Blaise Didier , Goncalves Anthony , Furst Sabine , Bay Jacques-Olivier , Faucher Catherine , Michallet Mauricette , Tabrizi Reza , Cahn Jean-Yves , Sirvent Anne , Mohty Mohamad , Chabannon Christian , Gravis Gwenaelle , Esterni Benjamin , Extra Jean-Marc , Viens Patrice 
Published: October 2019

Abstract
Despite continuous advances in the treatment of metastatic breast cancer, some patients have very poor outcome. Over the last period, we have investigated allogeneic immunotherapy as a possibility for tumor control. To date, we treated 31 pts with Allo SCT for advanced metastatic Breast Cancer (mBrC) in 2 successive clinical trials approved by Institut Paoli Calmette review Board, Marseille “comite de protection des personnes de Marseille” (local ethical committee) and the AFFSSAPS cellular therapies committee (national agency). The protocols were supported by special grants from the “Association pour la recherche sur le cancer (ARC)” (ARECA pole) and from the ministry of health (PHRC). All patients and donors gave informed consents. All pts (age: 43 (27–57)) underwent ASCT after the same reduced intensity conditioning (RIC) (Fludarabin (150mg/m2), Busulfan (8mg/kg) and Thymoglobulin (2,5mg/kg) or TLI (1 Cgy)) from a HLA-identical sibling (BM: 13%; PBSC: 87%) followed by CSA. All patients presented advanced disease as they have failed at least one conventional line of treatment. Indeed, prior to ASCT a median of 3 lines of treatment (1–7) have been administered over a period of 57 months (6–143). In addition, 15 (48%) pts underwent autologous SCT at a median time of 15 months (1–99) prior to ASCT. All pts were measurable and had a median of 2 metastatic sites (1–4) (liver:72%, bone:50%, lung:22% and brain:11%). We estimated disease status at transplant according to RECIST criteria: 17 (55%), 10 (32%) and 4 (13%) pts had progressive (PD), stable disease (SD) and partial response (PR) respectively. All patients engrafted. The cumulative incidences of grade 2–4 aGVHD and cGVHD were respectively 42% (25–59) and 62% (45–79) respectively. None of the 31 pts died from TRM. Seven patients achieved an objective response (CR=1; PR=6) at a median of 60 days (30–150) for a 24 % (9–39) OR cumulative incidence. Eventually all pts but 3 progressed at a median of 310 days (120–560) post transplant. Four pts are alive at median of 23 months (21–30) post transplant for a 2-year overall survival (OS) probability of 29% (16–47)). Results are dramatically different in regards to disease status at time of transplant. While outcome was uniformly poor for pts with PD (OR=0; 2 year OS probability: 6% (1–27)), patients with SD achieved a 40% (0–80) OR rate (p=.02) for a 50% (19–80) OS probability at 2 years (p=.001). Of the 4 patients in response at time of transplant, 3 increased their response (PR=2; CR=1) and 3 were alive after 2 years. This study shows that RIC-ASCT can be safely performed in BrC pts without high transplant related mortality. Data concerning quality of life (pre and post transplant) are presently under analysis. However we show evidences that pts with highly progressive disease do not benefit from this approach. In contrast, a high rate of response associated with prolonged survival can be achieved in patients with slowly progressive disease. These encouraging results for this advanced population compare favorably with non transplant literature. However most of the patients presenting objective response eventually progress. It seems that allogeneic immunotherapy could hardly cure patients with advanced mBrC. As routinely performed for acute myeloïd leukemia, this could perhaps be achieved only in pts in the initial disease phase when treatment disease resistance has not occurred. Target population would need careful selection on individual prognosis factors indicating their poor short term outcome: this represents the ultimate goal for future investigations. In this perspective, we designed a new program for the “triple negative” patients (Her2, estrogen and progesterone receptors negatives).