Chimeric antigen receptor-T cells (CAR-Ts) are an exciting new cancer treatment modality exemplified by the recent regulatory approval of two CD19-targeted CART therapies for certain B cell malignancies. However, this success in the hematological setting has yet to translate to a significant level of objective clinical responses in the solid tumor setting. The reason for this lack of translation undoubtedly lies in the substantial challenges raised by solid tumors to all therapies, including CART , that differ from B cell malignancies. For instance, intravenously infused CARTs are likely to make rapid contact with cancerous B cells since both tend to reside in the same vascular compartments within the body. By contrast, solid cancers tend to form discrete tumor masses with an immune-suppressive tumor microenvironment composed of tumor cells and non-tumor stromal cells served by abnormal vasculature that restricts lymphocyte infiltration and suppresses immune function, expansion, and persistence. Moreover, the paucity of uniquely and homogeneously expressed tumor antigens and inherent plasticity of cancer cells provide major challenges to the specificity, potency, and overall effectiveness of CART therapies. This review focuses on the major preclinical and clinical strategies currently being pursued to tackle these challenges in order to drive the success of CART therapy against solid tumors. Key Points Chimeric antigen receptor-T cell (CAR-T) therapy for the treatment of solid tumors is currently being evaluated in approximately one-third of all CART clinical trials. CART therapies targeting solid cancers have yet to demonstrate similar levels of clinical response as those being achieved in hematological indications. Developing methods and technologies to overcome the immune-suppressive tumor environment, tumor accessibility and infiltration, as well as optimization of CART function are the current focus of the CART field in order to improve therapy for solid tumors.

Although immunomodulatory drugs, alkylating agents, corticosteroids, protease inhibitors, and therapeutic monoclonal antibodies improve multiple myeloma outcomes, treatment burden is still an issue. Neutropenia is a known complication of cytotoxic cancer therapy and is often associated with infections; it is an important consideration in myeloma given the fact that patients often have a weakened immune system. The risk of febrile neutropenia increases with severe and persisting neutropenia. Recombinant granulocyte colony-stimulating factors (G-CSFs) are commonly used to reduce the incidence, duration, and severity of febrile neutropenia. Here, we review the risk and management of neutropenia associated with new and commonly used anti-myeloma agents. Few papers report the use of G-CSF in patients with multiple myeloma receiving anti-cancer treatments, and fewer describe whether G-CSF was beneficial. None of the identified studies reported G-CSF primary prophylaxis. Further studies are warranted to evaluate the need for G-CSF prophylaxis in multiple myeloma. Prophylaxis may be particularly useful in patients at high risk of prolonged severe neutropenia.Electronic supplementary materialThe online version of this article (10.1007/s00277-017-3191-7) contains supplementary material, which is available to authorized users.

74 Background: CYAD-101 is a first-in-class, non-gene edited allogeneic CAR T-cell product that combines the broad breadth of tumor targeting of the NKG2D-based chimeric antigen receptor (CAR) with a peptide-based approach that controls graft versus host disease (GvHD). NKG2D binds eight ligands commonly over-expressed across many tumors while the co-expressed T-cell receptor (TCR) inhibitory (TIM) peptide interferes with signaling by the endogenous TCR. A bank of CYAD-101 cells was produced from a single donor and evaluated in the AlloSHRINK phase 1 study (NCT03692429) in patients with unresectable metastatic colorectal cancer (mCRC). Methods: Three CYAD-101 infusions, each administered following a FOLFOX standard cycle as preconditioning chemotherapy, were tested in a 3+3 dose-escalation study (dose-levels (DL): 108, 3x108 and 109 T-cells per infusion) in patients with relapsed/refractory mCRC who progressed after previous treatment with oxaliplatin-based chemotherapy, with or without irinotecan-based chemotherapy. Results: Fifteen patients (pts) were enrolled (3 pts at DL-1, 3 pts at DL-2, 9 pts at DL-3). No dose-limiting toxicity (DLT), Grade ≥ 3 related adverse events or GvHD were reported after any of the CYAD-101 infusions, thus confirming the overall good safety profile of CYAD-101 post FOLFOX. Encouraging anti-tumor activity was observed with 2 confirmed partial responses (PR), including one response in a KRAS mutated patient. In addition, 9 pts achieved stable disease (SD), with 7 SD lasting at least 3 months. The median progression-free survival in this heavily pre-treated population was 3.9 months (95% CI). Whilst engraftment of the CYAD-101 cells was observed after each infusion, the relative level of systemic cytokines appeared to be primarily modulated by cell dose with some suggestion that the magnitude of modulation might be associated with clinical response. Interestingly, preliminary analysis of the T-cell repertoire identified some evidence of TCR diversity after therapy in the patient showing the most durable partial response. Conclusions: These clinical results demonstrate the safety and tolerability of a fist-in-human non-gene edited allogeneic CAR T-cell treatment with early promising anti-tumor activity in advanced mCRC pts. Preliminary translational analysis present intriguing observations that the modulation of systemic cytokine levels may be associated with dose which is uncommon in CAR T-cell therapies reported to date while limited T-cell clonal diversification in the best responding patient underscores the likely central role of the adoptively transferred T-cell in driving therapeutic response in this particular patient. Extension cohort evaluating CYAD-101 following other preconditioning chemotherapy is expected to be initiated end 2020. Clinical trial information: NCT03692429.

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CYAD-01 cells are engineered T-cells expressing a chimeric antigen receptor (CAR) based on the natural full-length human natural killer group 2D (NKG2D) receptor fused to the intracellular domain of CD3ζ. NKG2D receptor binds to 8 ligands (MICA/B, ULBP1-6) expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The hematological arm of the Phase I THINK study (NCT03018405) evaluates the safety and clinical activity of multiple CYAD-01 infusions (inf) without any prior preconditioning chemotherapy in r/r AML, MDS and multiple myeloma (MM) patients (pts). Three dose levels (DL) were evaluated: 3x108, 1x109 and 3x109 T-cells/inf. The first cycle of the treatment consists of 3 CYAD-01 infusions every 2 weeks and a potential 2nd cycle of 3 CYAD-01 infusions every 2 weeks if the patient is not in progressive disease (PD) at the end of the 1st cycle. Additional cohorts evaluate DL2 and DL3 following a denser treatment schedule for the 1st cycle of treatment, with the first 3 CYAD-01 infusions administered every week. As of end of July 2019, 16 pts were enrolled in the dose-escalation segment of the hematological cohort with the initial schedule (CYAD-01 infusions every 2 weeks) for 1st cycle, now completed. In total (uncleaned database), 7 pts experienced grade (G) 3/4 treatment-related adverse events (AEs). Cytokine release syndrome (CRS) occurred in 7 pts with only 2 pts at DL2 who experienced G3 CRS and 1 pt who experienced G4 CRS at DL3 reported as a dose-limiting toxicity (DLT). All CRS AEs resolved with early tocilizumab treatment. No treatment-related neurotoxicity AEs have been observed. Out of the 10 AML/MDS pts who received at least 3 CYAD-01 infusions and were assessed for clinical activity, 4 showed overall response (OR) at Day 29 of which 1 complete remission (CR) with partial hematologic recovery (CRh) for > 21 months in a r/r AML pt at DL1, 2 CR with incomplete hematologic recovery (CRi) for 1 month in AML pt at DL1 and DL3, and 1 marrow CR (mCR) for 1 month in an MDS pt at DL3. 2 AML pts at DL2 had stable disease (SD) for ≥ 3 months with bone marrow (BM) blast percentage decrease. Two other AML pts in DL3 achieved SD for at least 2 months. 2 AML pts did not have evidence of clinical response. The 2 evaluable MM pts did not show evidence of clinical response. As of end of July 2019, 8 pts were enrolled in cohorts with the dense schedule (4 in DL2 and 4 in DL3). Recruitment at 3x109 T-cells/inf. is still ongoing and is expected to be completed by the time of presentation. At DL2 (uncleaned database), only 1 pt out of 4 experienced a study treatment-related G4 AE (infusion related reaction). The 3 other pts experienced G1 or 2 study treatment-related AEs, with 3 pts who experienced G1/2 CRS. One AML pt reached a stable disease at the Day 32 tumor evaluation. At DL3, 2 out of 4 currently enrolled pts experienced study treatment related G3 AE (CRS) after their first CYAD-01 infusion. One of these G3 CRS was reported as a dose-limiting toxicity. Altogether, results obtained to date demonstrate an encouraging safety and tolerability profile of CYAD-01 without preconditioning chemotherapy in pts with r/r hematological malignancies. Encouraging anti-leukemic activity was observed in 6 out of 13 (46%) evaluable r/r AML/MDS pts in the THINK study, presenting relevant decrease in BM blasts. Four objective responses (1 CRh, 2 CRi, 1 mCR) were observed with the initial schedule. At DL2, the denser schedule did not modify the safety profile while increasing the area under the curve of CYAD-01 peripheral blood levels, which could suggest a possible impact on clinical activity at DL3, results expected by the time of presentation. Disclosures Sallman: Celyad: Membership on an entity's Board of Directors or advisory committees. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Awada:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Lilly: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EISAI: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genomic Health: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ispen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Lonez:Celyad: Employment. Lequertier:Celyad: Employment. Alcantar-Orozco:Celyad: Employment. Braun:Celyad: Employment. Flament:Celyad: Employment.