A phase 1 dose-escalation trial of intratumoral TTI-621, a novel immune checkpoint inhibitor targeting CD47, in subjects with relapsed or refractory percutaneously-accessible solid tumors and mycosis fungoides.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3101-TPS3101 ◽  
Author(s):  
John A. Thompson ◽  
Oleg Akilov ◽  
Christiane Querfeld ◽  
Matthew H. Taylor ◽  
Lisa Johnson ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Mycosis Fungoides ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Phase 1 ◽  
Macrophage Phagocytosis ◽  
The Impact

TPS3101 Background: CD47 is an immune checkpoint that binds to signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Tumor cells frequently overexpress CD47 and exploit this pathway to evade macrophage-mediated destruction. CD47 blockade promotes both innate (macrophage phagocytosis) and adaptive immunity (T cell responses). TTI-621 (SIRPαFc) is an immune checkpoint inhibitor designed to bind human CD47 and block the “do not eat” signal. The IgG1 region of TTI-621 engages Fcγ receptors on macrophages, converting the inhibitory signal to one that activates, thereby enhancing phagocytosis, and antitumor activity. A Phase 1 study is ongoing to evaluate the safety/tolerability and preliminary efficacy of IV administered TTI-621 in subjects with relapsed/refractory hematologic malignancies. It is hypothesized that employing direct intratumoral injections will result in very high local target engagement, promoting the development of innate and adaptive immune responses. Methods: A Phase 1 multicenter, open-label study was initiated to characterize the safety and tolerability of delivering TTI-621 directly into cancer lesions to achieve high local CD47 engagement to increase phagocytosis of tumor cells (NCT02890368). Subjects are being enrolled in sequential cohorts that gradually increase in dose and dosing frequency to characterize the feasibility of intratumoral TTI-621 injections and their safety, PK, pharmacodynamics, and preliminary antitumor activity. Eligible subjects are adults with relapsed or refractory percutaneously-accessible solid tumors or mycosis fungoides (MF), which have progressed on standard anticancer therapy or for which no other approved therapy exists. TTI-621 is delivered by intratumoral injection at protocol-defined doses and dosing regimens starting at 1 mg/injection. Serial biopsies are being collected to characterize local anti-tumor responses and assess the impact of TTI-621 on the tumor microenvironment. Clinical trial information: NCT02890368.

401 Phase 1/2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 with or without immune checkpoint inhibitor in patients with advanced HER2-expressing solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A426-A426
Author(s):  
Manish Sharma ◽  
Ecaterina Ileana Dumbrava ◽  
Richard Carvajal ◽  
Daniel Catenacci ◽  
Leisha Emens ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Phase 1 ◽  
List Type ◽  
Dependent Manner ◽  
Antibody Conjugates

BackgroundIn spite of advances made in the management of patients with HER2-expressing or -driven solid tumors, there remains a significant unmet need for novel approaches to improve patient outcomes. Intratumoral delivery of antitumor antibodies and immunostimulatory adjuvants such as toll-like receptor (TLR)7/8 agonists has been shown to activate tumor resident antigen-presenting cells (APCs), driving uptake, processing, and presentation of tumor neoantigens to T cells that mediate antitumor immunity. BDC-1001 is delivered systemically and has demonstrated superior preclinical biology. This novel ISAC consists of an investigational biosimilar of the humanized monoclonal antibody trastuzumab chemically conjugated to a TLR7/8 agonist with a non-cleavable linker. BDC-1001 activates human myeloid APCs in addition to retaining antibody-mediated effector functions such as antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). Studies in trastuzumab-resistant xenograft models and syngeneic tumor models indicate that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, leading to complete tumor regression in a TLR- and Fc receptor-dependent manner.1 2 Importantly, BDC-1001 did not induce interstitial lung disease, cytokine release syndrome, or thrombocytopenia in non-human primate studies. A four-part phase 1/2, first-in-human study has been initiated that evaluates BDC-1001 with or without (±) an immune checkpoint inhibitor targeting PD-1 in patients with HER2-expressing or HER2-amplified advanced/metastatic solid tumors.MethodsThis dose-escalation and dose-expansion study is enrolling up to 390 patients with HER2-expressing (IHC2+ or 3+ protein, irrespective of gene amplification) or HER2-amplified (by in situ hybridization or next-generation sequencing) advanced solid tumors. Primary objectives of the dose-escalation phase are to define safety and tolerability and determine the recommended phase 2 dose of BDC-1001 as monotherapy (Part 1) and in combination with an immune checkpoint inhibitor (Part 2). Part 2 is planned to start once BDC-1001 safety data are available. Primary endpoints include incidence of 1) adverse events and serious adverse events; 2) dose-limiting toxicities within a 3+3 design; and 3) potential immune-related toxicities. The dose-expansion portion of the trial will evaluate preliminary antitumor activity of BDC-1001 alone (Part 3) and in combination with an immune checkpoint inhibitor (Part 4). Secondary objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers in tumor tissue and in peripheral blood associated with drug exposure. These exploratory studies will help elucidate the mechanism of action and seek to identify biomarkers associated with BDC-1001 biological activity with or without immune checkpoint inhibitor. This global study is currently recruiting patients.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov (NCT04278144).Ethics ApprovalThe study and the protocol were or will be approved by the Institutional Review Board or ethics committee at each site.ConsentN/AReferencesAckerman, et al. TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation leading to enhanced effector function and anti-tumor immunity in pre-clinical models. Cancer Res. 2019:79 [13 Suppl]:Abstract 1559.Ackerman, et al. HER2-targeting TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation and anti-tumor immune responses in a TLR- and FcR- dependent manner. J Immunother Cancer 2019;7:283

scholarly journals Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002181
Author(s):  
Erin F Simonds ◽  
Edbert D Lu ◽  
Oscar Badillo ◽  
Shokoufeh Karimi ◽  
Eric V Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Prolonged Survival ◽  
Tumor Associated Macrophages ◽  
The Brain ◽  
Immune Profiling

BackgroundGlioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed.MethodsWe used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations.ResultsICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation.ConclusionsOur data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.

The emerging use of immune checkpoint blockade in the adjuvant setting for solid tumors: a review

Immunotherapy ◽  
2019 ◽  
Vol 11 (16) ◽  
pp. 1409-1422 ◽  
Author(s):  
Elissar Moujaess ◽  
Fady Gh Haddad ◽  
Roland Eid ◽  
Hampig Raphael Kourie
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Adjuvant Setting ◽  
Lung Cancers ◽  
Metastatic Setting ◽  
Postoperative Setting

The use of immune checkpoint inhibitors has been approved in the advanced and metastatic setting for many types of solid tumors. Nonetheless, their role in the adjuvant setting is limited to the treatment of surgically resected melanoma. Ipilimumab was the first immune checkpoint inhibitor approved for this indication, followed by nivolumab and pembrolizumab. Many ongoing trials are evaluating these molecules in the postoperative setting, alone or in combination with other therapies. Preliminary results are promising regarding the treatment of other cutaneous tumors, lung cancers, head and neck squamous cell carcinomas, bladder cancer and renal cell carcinomas. Some data assessing their use for the adjuvant treatment of esophageal, colorectal, ovarian cancer and other solid tumors are similarly emerging.

scholarly journals Enterococcus peptidoglycan remodeling promotes immune checkpoint inhibitor therapy

2020 ◽  
Author(s):  
Matthew E. Griffin ◽  
Juliel Espinosa ◽  
Jessica L. Becker ◽  
Jyoti K. Jha ◽  
Gary R. Fanger ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Mouse Tumor ◽  
Peptidoglycan Hydrolases ◽  
Checkpoint Inhibitor Therapy ◽  
Specific Species

AbstractThe antitumor efficacy of cancer immunotherapy has been correlated with specific species within the gut microbiota. However, molecular mechanisms by which these microbes affect host response to immunotherapy remain elusive. Here we show that specific members of the bacterial genus Enterococcus can promote anti-PD-L1 immunotherapy in mouse tumor models. The active enterococci express and secrete orthologs of the NlpC/p60 peptidoglycan hydrolase SagA that generate immune-active muropeptides. Expression of SagA in non-protective E. faecalis was sufficient to promote antitumor activity of clinically approved checkpoint targets, and its activity required the peptidoglycan sensor Nod2. Notably, SagA-engineered probiotics or synthetic muropeptides also promoted checkpoint inhibitor antitumor activity. Our data suggest that microbiota species with unique peptidoglycan remodeling activity may enhance immunotherapy and could be leveraged for next-generation adjuvants.One Sentence SummaryA conserved family of secreted NlpC/p60 peptidoglycan hydrolases from Enterococcus promote antitumor activity of immune checkpoint inhibitors.

scholarly journals Application of Immune Checkpoint Inhibitors in the Treatment of Cholangiocarcinoma

2021 ◽  
Vol 20 ◽  
pp. 153303382110399
Author(s):  
Fan-li Zeng ◽  
Jing-fang Chen
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Malignant Tumors ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
General Term ◽  
Distal Cholangiocarcinoma ◽  
Poor Outcomes ◽  
Defective Mismatch Repair

Cholangiocarcinoma is a general term for intrahepatic and extrahepatic malignant tumors deriving in the biliary system. According to the location, it is divided into intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma. Progressive cholangiocarcinoma yields poor outcomes with radiotherapy; therefore, there is an urgent need for new therapeutic breakthroughs. Immune checkpoint inhibitor (ICI) therapy brings the treatment for cancer into a new field, with the use of drugs targeting PD-1/PD-L1 and CTLA-4 considerably extending the survival of patients with melanoma, lung cancer, and other solid tumors. The FDA has approved the application of pembrolizumab for solid tumors with high microsatellite instability and defective mismatch repair, including cholangiocarcinoma. Moreover, the combination of ICIs with chemotherapy and radiation therapy showed good promise. The aim of the present study was to review the application of ICIs in the treatment of cholangiocarcinoma and to summarize the reported individualized immunotherapy-based protocols and ongoing clinical trials for clinical reference.

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