CD19-targeted chimeric antigen receptor (CAR) modified T cell immunotherapy is a novel treatment with promising results in patients with relapsed/refractory lymphoid malignancies. CAR T cell therapy has known early toxicities of cytokine release syndrome and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have used patient-reported outcomes, including Patient-Reported Outcomes Measurement Information System (PROMIS) measures, to assess neuropsychiatric and other patient-reported outcomes of 40 patients with relapse/ refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and acute lymphoblastic leukemia 1 to 5 years after treatment with CD19-targeted CAR T cells. Mean T scores of PROMIS domains of global mental health, global physical health, social function, anxiety, depression, fatigue, pain, and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 patients (47.5%) reported at least 1 cognitive difficulty and/or clinically meaningful depression and/or anxiety, and 7 patients (17.5%) scored 40 in global mental health, indicating at least 1 standard deviation worse than the general population mean. Younger age was associated with worse long-term global mental health (P = .02), anxiety (P = .001), and depression (P= .01). Anxiety before CAR T cell therapy was associated with increased likelihood of anxiety after CAR T cell therapy (P = .001). Fifteen patients (37.5%) reported cognitive difficulties after CAR T cell therapy. Depression before CAR T cell therapy was statistically significantly associated with higher likelihood of self-reported post-CAR T cognitive difficulties (P = .02), and there was a trend for an association between acute neurotoxicity and self-reported post-CAR T cognitive difficulties (P = .08). Having more post-CAR T cognitive difficulties was associated with worse global mental health and global physical health. Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR T cell therapy. However, nearly 50% of patients in the cohort reported at least 1 clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty), indicating that a significant number of patients would likely benefit from mental health services following CAR T cell therapy. Younger age, pre-CAR T anxiety or depression, and acute neurotoxicity may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings.

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies; however, it is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high-grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this deficit, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov; NCT01865617), with primary end points of absolute neutrophil count and platelet count at day-28 after CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75%, respectively, at 28 days after infusion. Hematologic toxicity was noted in a significant subset of patients, with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Using debiased least absolute shrinkage selector and operator regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower prelymphodepletion platelet count as an independent predictor of both decreased neutrophil and platelet counts after CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of interleukin-6 and lower day-28 cell counts; in contrast, higher serum concentrations of transforming growth factor-β1 were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery after CD19 CAR T-cell therapy.

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TPS79 Background: CAR-T cells have demonstrated marked tumor regression in patients (pts) with hematologic malignancies. ROR1, a tyrosine kinase orphan receptor, is expressed in triple negative breast cancers (TNBC) and non-small cell lung cancers (NSCLC) and is a novel candidate for CAR-T cell therapy. ROR1-specific CAR-T cells are engineered with lentiviral vector encoding ROR1 scFv/4-1BB/CD3ζ and a truncated EGFR molecule to permit elimination of ROR1 CAR-T cells in case of toxicity. Methods: NCT02706362 is a phase I study evaluating the safety and anti-tumor activity of adoptively transferred autologous ROR1 CAR-T cells in pts with advanced ROR1+ TNBC and NSCLC. Eligibility criteria include: metastatic TNBC or NSCLC; measurable disease; prior standard therapy with no maximum on number of prior regimens; tumor ROR1 expression > 20% by IHC; KPS > 70%; age ≥18; negative pregnancy test for women of childbearing potential; informed consent; adequate organ function. Exclusions are: active autoimmune disease or uncontrolled infection, HIV seropositive status, contraindication to cyclophosphamide, anticipated survival < 3 months, and/or untreated CNS metastases. After screening, leukapheresis is performed, CD8+ and CD4+ T cells are selected, then transduced with the ROR1+ CAR lentivirus and expanded. Lymphodepletion with cyclophosphamide and fludarabine is followed 36-96 hours later by infusion of ROR1 CAR-T cells in escalating doses (3.3 x 105/kg - 1 x 107/kg cells with defined CD8+ and CD4+ composition). Pts are treated in cohorts of 2 to determine cell dose associated with an estimated toxicity rate of < 25%. Primary aim is to determine the maximum tolerated dose (MTD) and safety of ex vivo expanded ROR1 CAR-T cells. Secondary aims include persistence and phenotype of transferred T cells, trafficking of T cells to tumor site, in vivo function, and preliminary antitumor activity of ROR1 CAR-T cells by RECIST 1.1. Dose escalation is determined by CRM algorithm with minimum of 21-day interval following infusion between pts. Preliminary estimates of efficacy will be obtained among all pts and those treated at estimated MTD. Six of 30 pts have been enrolled with no DLTs observed. Clinical trial information: NCT02706392.

BACKGROUND: ROR1 is a type 1 transmembrane tyrosine kinase receptor that plays a critical role in embryonic and fetal development. ROR1 has been described as a possible oncogene and is expressed in numerous malignancies including TNBC and non-small cell lung cancer (NSCLC). We are conducting a first-in-human trial targeting ROR1 with CAR-T cells in patients with advanced TNBC and NSCLC. The cellular construct employed targets the Ig/Fz portion of the extracellular domain of ROR1 and contains 4-1BB/CD3ζ intracellular signaling domain. The manufacturing process utilizes autologous peripheral blood lymphocytes, separated into CD4 and CD8 subsets, which are independently cultured with anti-CD3/anti-CD28 beads and IL-2, then transduced with a lentiviral vector encoding the ROR1 CAR. The CAR-T cell product is formulated in a 1:1 ratio of CD4+ and CD8+ CAR-T cells. METHODS: This ongoing phase I trial (NCT02706392) is evaluating the safety of administering ROR1 CAR-T cells in escalating doses (3.3x105, 1x106, 3.3x106 and 1x107 cells/kg) following lymphodepletion with cyclophosphamide-containing regimens using a continual reassessment method (CRM) for dose escalation. TNBC patients with adequate organ function and performance status, measurable disease, and tumors expressing ROR1 (&gt;20% by IHC) are eligible for enrollment. Persistence of CAR-T cells in blood, cytokine levels, measures of immunogenicity and multi-parametric flow cytometry are being evaluated at multiple time points. Imaging assessments by RECIST 1.1 are performed day 28 - 90, then at 6 and 12 months, and every 6 months as clinically indicated to estimate efficacy. RESULTS: To date, 4 TNBC patients (age range 38-67) have been enrolled, treated and are evaluable for response. Patients had received prior therapies for metastatic disease (range 3-11). 3 of 4 had visceral metastases. No dose-limiting toxicities, severe neurotoxicity or severe cytokine release syndrome (sCRS) were observed at dose levels 1 and 2. Two patients experienced grade 1 CRS. 2 of 4 patients had evidence of CAR-T cell expansion between days 14 and 20, with peak CD8+ CAR-T up to 232.1 cells/uL. Analysis of surface phenotype revealed upregulation of inhibitory receptors on CAR-T cells at the peak of expansion, confirmed by RNA seq. Post-treatment tumor biopsy in patient with partial response revealed an influx of CD3+ T cells and macrophages suggesting ROR1 CAR-T cell trafficking. Two patients received 2 CAR-T cell infusions. Two patients had confirmed stable disease at 15 weeks and 19 weeks, respectively. One patient has stable disease after 1st CAR-T cell infusion, then confirmed partial response after 2nd CAR-T cell infusion which has persisted for 14 weeks. Results will be updated. CONCLUSIONS: ROR1+ CAR-T cells can be safely transferred, expand in vivo in patients with TNBC. Current efforts are directed at understanding and overcoming the mechanisms that limit homing, persistence, and/or function at tumor sites. The trial is continuing with dose-escalation. Funding provided by 8RO1 CA114536-11 and Juno Therapeutics. Citation Format: Specht JM, Lee SM, Turtle C, Berger C, Balakrishnan A, Srivastava S, Viollet V, Veatch J, Gooley T, Mullane E, Chaney CN, Rader C, Pierce RH, Gottardo R, Maloney DG, Riddell SR. A phase I study of adoptive immunotherapy for ROR1+ advanced triple negative breast cancer (TNBC) with defined subsets of autologous T cells expressing a ROR1-specific chimeric antigen receptor (ROR1-CAR) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-13.