CD137 mAb / Mayo Clinic, LFB SA - LARVOL DELTA

Combination IO+IO (IASLC-WCLC 2018) - "...In NSCLC, Pembrolizumab monotherapy in patients with high PD-L1 expression showed significant improvement of overall survival (OS) compared with platinum doublets as first-line therapy...The PFS was significantly improved with combination of nivolumab plus ipilimumab compared with chemotherapy alone (HR=0.74, 95% CI;0.58-0.94), but the benefit from nivolumab plus ipilimumab combination was confined only in patients with TMB 10 mut/Mb suggesting TMB can be considered predictive biomarker for combination of nivolumab plus ipilimumab. In contrast, the MYSTIC study, which compared durvalumab plus tremelimumab with platinum-based chemotherapy, did not meet the primary endpoint of PFS...Similarly, antibodies targeting co-inhibitory molecules, such CD28, OX40, GITR, CD137 or CD27 combined with anti-PD1 or anti-PDL1 are also underway for early clinical trial (Table 1)...Further, it will be long way to go to determine which combination is the most effective among others. ..."

Tumor mutational burden • Melanoma • Non Small Cell Lung Cancer

Debate: Transplant is Still Necessary in the Era of Targeted Cellular Therapy for ALL (SOHO 2019) - P1/2; "The CAR consists of the single-chain variable fragment of the antibody (scFv) targeted to a tumor-associated antigen which is recognized in an MHC-independent fashion; the scFv is coupled via an extra-cellular hinge domain and transmembrane domain to an intracellular signaling domain, typically the CD3ζ chain of the T cell receptor.7 Autologous T-cells are collected from peripheral blood via venipuncture or apheresis procedure and transduced with the CAR construct via a lentiviral or retroviral vector, or using electroporation and a transposon/transposase system.8 Cells are cultured and expanded ex vivo either using CD3/28 beads or artificial antigen-presenting cells and specific cytokines prior to infusion.9,10 CAR-Ts persistence and clinical activity in vivo can be enhanced by the addition of a co-stimulatory molecule to the CAR construct (second generation CAR), usually CD28 or CD137 (4-1BB).11-13 An initial report in a highly-refractory CLL patient treated with a..."

IO biomarker • PD(L)-1 Biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • FAS • IL15

ZUMA-11: A Phase 1/2 Multicenter Study of Axicabtagene Ciloleucel (Axi-Cel) + Utomilumab Patients with Refractory Large B Cell Lymphoma (ASH 2019) - "Activation of the costimulatory receptor 4-1BB (CD137) on CAR T cells may enhance axi-cel antitumor activity by enhancing T cell proliferation, function, and survival. This study uses a single-arm design to estimate the true CR rate; with a sample size of 27 patients, of which ≤ 3 patients will have been treated in the Phase 1 portion, the maximum half-width of the 95% confidence interval about response will be ≥ 21%. ZUMA-11 is open and accruing patients."

Clinical • P1/2 data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation

Phase 1 study of COM701 monotherapy and in combination with nivolumab in patients with advanced solid tumors. (SITC 2019) - "Key Inclusion Criteria: Age >=18 years, histologically confirmed advanced solid tumor, performance status ECOG 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137 treatments are permissible. Assessment of safety and tolerability is ongoing for all patients. Updated results will be presented at the congress."

Clinical • Combination therapy • Monotherapy • P1 data • Oncology • Solid Tumor

Immunogenicity risk assessment for biotherapeutics through in vitro detection of CD134 and CD137 on T helper cells. (PubMed, MAbs) - "This method provides a rapid and simple preclinical test of the immunogenic potential of a new candidate biotherapeutic or biosimilar. Implementation of this approach during biotherapeutic research and development enables rapid elimination of candidates that are likely to cause ADA-related adverse events and detrimental consequences."

IO biomarker • Journal • Preclinical • CD4 • TNFRSF4 • TNFRSF9

Immunostimulatory and oncolytic properties of rotavirus can overcome resistance to immune checkpoint blockade therapy (AACR 2018) - "...IT rotavirus vaccines was associated to an increase of myeloid infiltrating cells expressing up-regulated level of CD86 in the tumor microenvironment, and upregulation of activation markers such as OX40/CD137 on T cells...Therefore, in situ immunization strategies with IT attenuated rotavirus can be implemented quickly in the clinic including in pediatric cancers. IT priming of the anti-tumor immunity with oncolytic and immunostimulatory rotavirus vaccines could be a feasible strategy to overcome resistance to anti-PD-1/anti-CTLA-4 therapy in patients with cancer."

Checkpoint inhibition • IO Biomarker • PD(L)-1 Biomarker • Lymphoma • Neuroendocrine Tumor

Tumor-restricted immune modulation by multispecific molecules from the DARPin toolbox (AACR 2018) - "...We generated DARPin molecules that bind with high affinity to TNFR-superfamily members (CD134, CD137 and CD40) and DARPin molecules that bind to tumor-specific antigens such as HER2 and EGFR or targets restricted to the tumor stroma compartment like FAP and extra-domain B of fibronectin (ED-B)...These finding were confirmed in experiments with primary immune cells where we see immune-cell activation only upon binding to the tumor-localizing target. This could be shown for multiple combinations (>8) and supports the concept that multi-specific DARPin molecules are powerful drug-candidates allowing tumor-restricted immune cell activation."

IO Biomarker • PD(L)-1 Biomarker • Oncology

[VIRTUAL] A third-generation human GUCY2C-targeted CAR-T cell for colorectal cancer immunotherapy (SITC 2020) - "Our CAR utilizes a single chain variable fragment of human origin directed towards the extracellular domain of GUCY2C, the CD28 hinge, transmembrane, and intracellular signaling domain (ICD), 4-1BB (CD137) ICD, and CD3ζ ICD...We hypothesize that GUCY2C-directed CAR-T cells present a viable therapeutic option for metastatic CRC. In vivo animal models to examine this potential are currently on-going."

CAR T-Cell Therapy • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • IFNG • IL15 • IL7 • MSI • TNFA

[VIRTUAL] A third-generation human GUCY2C-targeted CAR-T cell for colorectal cancer immunotherapy (SITC 2020) - "Our CAR utilizes a single chain variable fragment of human origin directed towards the extracellular domain of GUCY2C, the CD28 hinge, transmembrane, and intracellular signaling domain (ICD), 4-1BB (CD137) ICD, and CD3ζ ICD...We hypothesize that GUCY2C-directed CAR-T cells present a viable therapeutic option for metastatic CRC. In vivo animal models to examine this potential are currently on-going."

CAR T-Cell Therapy • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • IFNG • IL15 • IL7 • MSI • TNFA

Posttransplant cyclophosphamide as a platform for immunotherapy after allogeneic stem cell transplantation for multiple myeloma (IMMUNOLOGY 2020) - "Allogeneic stem cell transplantation (alloSCT) is a highly effective, curative therapy for leukemia yet does not provide a survival benefit above autologous SCT in patients with multiple myeloma (MM). Subsequent administration of CD137 agonists enhanced T cell activation and cytolytic activity within bone marrow, without exacerbating GVHD. Thus, PT-Cy provides a platform for optimizing immunotherapy after alloSCT."

IO Biomarker • CD8 • CSF1 • CSF1R • MLL • PD-L1

Digital spatial mapping of the immune landscape of triple negative breast cancer reveals novel features of immune-tumor cell interaction (SABCS 2019) - "Samples were matched for patient characteristics, treatment arm (capecitabine vs. 5-fluorouracil), and outcome based on recurrence-free survival (RFS) with 22 samples from patients who recurred and 22 samples from patients with durable RFS...In both tumor and stroma segments, over-expression of T cell activation markers (CD137, GITR) was associated with better outcome, whereas T cell markers (CD3, CD4, CD8) were not significantly associated with outcome... Using an in-depth analysis to precisely quantify the abundance of multiple immune function proteins in a spatially defined manner, we observed that PD-L2, IDO1, and T cell activation markers were robustly associated with durable RFS in both tumor and stromal segments. In contrast, MHC components (HLA-DR, beta-2-microglobulin), B cell markers (CD20), and NK cell markers (CD56) were strongly associated with favorable outcome in tumor but not in stromal segments. Our study highlights the conclusion that the immune..."

IO Biomarker • B2M • CD27 • CD40 • Cytokeratin • IDO1 • NCAM1

MANAGING THE TOXICITIES OF CAR T‐CELL THERAPY (ICML 2019) - "...Axicabtagene ciloleucel (axi-cel)1 and tisagenlecleucel2 are both approved for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma...However, the co-stimulatory domains used to provide signal 2 are different with axi-cel using CD28 and tisagenlecleucel and liso-cel using 4-1BB (CD137)...Tocilizumab may be administered if there is concurrent CRS...In addition, if the conditioning therapy included fludarabine, prophylaxis against herpes zoster and pneumocystis jiroveci pneumonia is recommended for at least 1 year...Innovative design of CARs including tunable CARs that allow control of the rate of expansion and activity of CAR T cells in vivo may further improve the safety of these therapeutic products. repeated on Friday, June 21, in Auditorium (USI Università)"

CAR T-Cell Therapy

MANAGING THE TOXICITIES OF CAR T‐CELL THERAPY (ICML 2019) - "...Two anti-CD19 CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved for the management of relapsed/refractory large B-cell lymphoma after two lines of systemic therapy...However, the co-stimulatory domains used to provide signal 2 are different with axi-cel using CD28 and tisagenlecleucel and liso-cel using 4-1BB (CD137)...In addition, if the conditioning therapy included fludarabine, prophylaxis against herpes zoster and pneumocystis jiroveci pneumonia is recommended for at least 1 year...Current management strategies are focused on careful monitoring, early recognition of toxicities, and prompt intervention with supportive care for low-grade toxicities and tocilizumab and/or corticosteroids for severe toxicities. It is possible that in the future, prophylactic strategies may mitigate the toxicities without compromising efficacy. Innovative design of CARs including tunable CARs that allow control of the rate of expansion and activity..."

CAR T-Cell Therapy

Identification of pre-existing neoantigen-specific T cells in patients receiving checkpoint inhibitor therapy using a deep learning antigen prediction model (AACR 2019) - "...In addition, antigen-reactive T cells were sorted for single cell sequencing on the 10x platform using CD137 as an HLA-independent T-cell activation marker. In summary, pre-existing neoantigen specific T cells and TCR clones can be rapidly identified utilizing routine clinical specimens, through (i) a powerful neoantigen prediction model, (ii) short-term in vitro T-cell expansion followed by IFN-gamma ELISpot, and (iii) HLA-independent selection and single cell sequencing. This methodology may allow rapid design of neoantigen-targeting vaccines or selection of TCRs for cell therapeutic approaches."

Checkpoint inhibition • Clinical • IO Biomarker • Tumor Mutational Burden • Tumor-specific neoantigens