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CAR-T cells represent a new approach to anti-tumor cellular immunotherapy allowing to combine the recognition of tumor antigens on target cells and the activation, proliferation and cytotoxic capacity of T lymphocytes. Impressive clinical results have been obtained with CAR-T cells targeting the CD19 antigen in relapsing or refractory B cell malignant lymphomas or acute lymphoblastic leukemias, with complete response rates of 40 to 90%. However, 30 to 50% of responding patients in B malignancies will escape treatment secondarily, and the effectiveness of these approaches in solid tumors remains limited. Different mechanisms of primary resistance and/or escape to CAR-T cells have been described. This review aims to describe these mechanisms and explore potential ways for optimization. We will see that the initial response and its long-term persistence depends on several parameters: the functional characteristics of the CAR-T cells in vivo, the expression of targeted antigens on tumor cells, the development of a immunosuppressive microenvironment. Or of an immune response directed against the CAR molecule. In solid tumors in particular, the specificity of the antigen target and the "homing" of CAR-T cells in the tumor site are additional elements to consider. A better knowledge of mechanisms of resistance will help to improve the clinical outcomes by either modulating the construction and the production of CAR-T cells and/or to combine them with other immunotherapeutic approaches to better control the tumor microenvironment.

Background Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008. Patients and methods We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2−; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD). Results The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2– MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2– and TNBC cohorts, respectively, whatever YOD. Conclusion OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed., Highlights • OS of HER2+ MBC patients keeps improving over time [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. • This effect seems timely related to the release of drugs demonstrated to improve survival in clinical trials. • OS gains observed in real life among HER2+ MBC patients are at least equivalent to those observed in clinical trials. • YOD had no sustained impact on OS among patients with TNBC and luminal MBC. • The impact of CDK4/6 inhibitors cannot yet be assessed in this cohort.

Introduction Clonal selection is one of the mechanisms leading to therapy-related myeloid neoplasms (TRMN). A preexisting somatic mutation in hematopoietic stem cell (defined as clonal hematopoiesis [CH]) emerges under pressure of chemotherapy or radiotherapy, leading to TRMN development. Most of these mutations belong to the DNA damage response (DDR) pathway as TP53 or PPM1D mutations and are known to confer a dismal prognosis. Recently authorized for the treatment of ovarian cancers (OC), the poly (ADP-ribose) polymerase inhibitors (PARPi) represent a promising targeted therapy. However, by inducing DNA damage and altering DNA repair process, PARP inhibition could represent a challenge for the genetic stability of the healthy tissues. Thus, we assessed the effect of PARP inhibition on the development of CH and TRMN after PARPi treatment for OC (TRMN-PARPi) in combination with chemotherapies. Methods Firstly, we performed a targeted 77 genes mutational analysis using Next Generation Sequencing (NGS) in 13 patients exposed to PARPi without TRMN. Secondly, we retrospectively identified, with the help of the UNIHEM group of Unicancer, 17 patients who experienced TRMN-PARPi. Clinical, biological and survival data were collected and compared to 23 OC patients with TRMN not treated with PARPi (Gustave Roussy institutional database). Lastly, NGS was performed for 3 patients with TRMN-PARPi with sequential sampling. Patient's samples were obtained with informed consent. Results Thirteen OC patients during maintenance treatment with PARPi without TRMN were explored by NGS. Median age at NGS was 64.5 years old (yo) (40.5-75.3). 4/13 (31%) patients harbored BRCA1/2 germline mutation. Time between OC diagnosis and NGS was 4.3 y (1-11.6). The median number of chemotherapy line at PARPi initiation was 2 (1-3). 7 received Olaparib, 5 Niraparib and 1 Rucaparib. The median duration of PARPi treatment before NGS was 4.7 months (1.1-25.1). 12/13 patients experienced hematological toxicities during the PARPi treatment. CH was found in 10/13 (77%) patients (Figure 1a), including mutations of DDR genes in 8/10 (80%). 6/8 (75%) patients had 2 or more gene mutations. Next we identified 17 cases of TRMN occurring during or after PARPi administration for OC (6/17 [35%] t-AML and 11/17 [65%] t-MDS). 12/17 (71%) patients had BRCA germline mutations (7 BRCA1 and 5 BRCA2). All received Olaparib with a median dose of 600mg/d (400-1200). Median duration of Olaparib treatment was 1.7 years (0.2-4.6). TRMN-PARPi were described 1.4 months (0-10.9) after the end of PARPi administration. We compared these patients to a cohort of TRMN post OC not treated by PARPi. Number of therapy lines for OC, time between TRMN and OC diagnosis, median age at TRMN, were, for TRMN-PARPi, 2 (1-8), 5.9 y (0.9-20.8), 64.4 yo (46-74); respectively, compared to 3 (1-8), 4.9 y (1.7-36.9), 59.3 yo (35.7-85.7); (p=ns). TRMN-PARPi cytogenetic was unfavorable for 16/17 (94%) (including 11/17 [65%] complex karyotype) compared to 16/23 (70%) (11/23 [48%] complex karyotype). C Median survival was significantly lower in the TRMN-PARPi group 3.9 months 95%CI [2.0-9.7] and 6.1 months 95%CI [4.1-15.8] respectively, p=0.046, Fig 1b). However, median survival from OC diagnosis was not different between the two groups 6.2 y 95%CI [5.6-NA] for TRMN-PARPi vs 5.6 y 95%CI [5.0-11.6]. NGS was available for 8/17 TRMN-PARPi and revealed mutations in DDR genes in 7/8 patients (6 patients with TP53 mutation, 2 with PPM1D mutation). For 3 patients, we had samples from OC stage, before PARPi administration. We found that mutations from TRMN stage were present at lower frequency, confirming clonal selection by PARPi treatment (Figure 1c). Conclusions Here we described, for the first time, a cohort of TRMN patients previously treated with PARPi for an OC. Intriguingly, most of these TRMN occurred with a short latency at the end of PARPi treatment, with unfavorable cytogenetic and very short OS. Moreover, we found a very high percentage of CH involved in the DDR pathway (62%) in patients under PARPi treatment without TRMN suggesting a potential clonal selection which could lead ultimately to TRMN. PARPi are now indicated in 1rst line high grade OC regardless of BRCA status, which should expand indications. Benefit for OC patients is not questionable; however, caution will be warranted for patients with CH before PARPi treatment, especially implicating DDR mutations. Disclosures Etienne: Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.