Intralesional Injection of the CD47-blocking immune checkpoint inhibitor TTI-621 (SIRPaFc) induces antitumor activity in patients with relapsed/refractory mycosis fungoides and Sézary syndrome: Interim results of a multicenter Phase 1 trial

2018 ◽  
Vol 101 ◽  
pp. S34 ◽  
Author(s):  
Christiane Querfeld ◽  
John A. Thompson ◽  
Matthew Taylor ◽  
Raju Pillai ◽  
Lisa DS. Johnson ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Mycosis Fungoides ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Phase 1 ◽  
Intralesional Injection ◽  
Sézary Syndrome ◽  
Phase 1 Trial ◽  
Multicenter Phase

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.

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.

Impact of immune checkpoint inhibitor dose on toxicity, response rate, and survival: A pooled analysis of dose escalation phase 1 trials.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 3077-3077 ◽  
Author(s):  
Shiraj Sen ◽  
Kenneth R. Hess ◽  
David S. Hong ◽  
Aung Naing ◽  
Le Huang ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Response Rate ◽  
Checkpoint Inhibitor ◽  
Phase 1 ◽  
Pooled Analysis ◽  
Phase 1 Trials ◽  
Toxicity Response ◽  
Inhibitor Dose

A phase 1 study of TTI-621, a novel immune checkpoint inhibitor targeting CD47, in subjects with relapsed or refractory hematologic malignancies.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. TPS7585-TPS7585 ◽  
Author(s):  
Stephen Maxted Ansell ◽  
Robert W. Chen ◽  
Ian Flinn ◽  
Michael B. Maris ◽  
Owen A. O'Connor ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Phase 1 Study

Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study

2021 ◽  
Author(s):  
Christiane Querfeld ◽  
John A Thompson ◽  
Matthew H Taylor ◽  
Jennifer A DeSimone ◽  
Jasmine M Zain ◽  
...  
Keyword(s):  
Mycosis Fungoides ◽  
Immune Checkpoint ◽  
Phase 1 ◽  
Innate Immune ◽  
Sézary Syndrome ◽  
Sezary Syndrome ◽  
Phase 1 Study ◽  
Multicentre Phase

Abstract 3291: Development of a novel prognostic scoring system for patient selection in immune checkpoint inhibitor phase 1 clinical trials

2017 ◽  
Author(s):  
Shiraj Sen ◽  
Kenneth Hess ◽  
David Hong ◽  
Aung Naing ◽  
Sarina Piha-Paul ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Patient Selection ◽  
Immune Checkpoint ◽  
Scoring System ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Phase 1

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

Lichenoid dermatitis from immune checkpoint inhibitor therapy: An immune‐related adverse event with mycosis‐fungoides‐like morphologic and molecular features

2019 ◽  
Vol 46 (11) ◽  
pp. 872-877 ◽  
Author(s):  
Michael T. Tetzlaff ◽  
Sherry Tang ◽  
Taylor Duke ◽  
Daniel A. Grabell ◽  
Maria E. Cabanillas ◽  
...  
Keyword(s):  
Adverse Event ◽  
Mycosis Fungoides ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Inhibitor Therapy ◽  
Related Adverse Event ◽  
Molecular Features ◽  
Checkpoint Inhibitor Therapy
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