Faculty Opinions recommendation of Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody.

2007 ◽  
Author(s):  
Michael Schön
Keyword(s):  
Monoclonal Antibody ◽  
Cancer Patients ◽  
Immune Modulation ◽  
Clinical Activity

Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2507-2507 ◽  
Author(s):  
R. H. Vonderheide ◽  
K. T. Flaherty ◽  
M. Khalil ◽  
M. S. Stumacher ◽  
D. L. Bajor ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Solid Tumors ◽  
Immune Modulation ◽  
Critical Role ◽  
Clinical Activity ◽  
Cytokine Release ◽  
Mhc Molecules ◽  
Grade 3 ◽  
Dose Levels

2507 Background: The cell-surface molecule CD40 plays a critical role in activating antigen presenting cells (APC) and mediates upregulation of costimulatory and MHC molecules, cytokine release, and enhancement of tumor immunity. CD40 is also expressed by 30%-70% of solid tumors, and engagement of CD40 on tumor cells results in apoptosis. CP-870,893 - a fully human and selective CD40 agonist monoclonal antibody - activates human APC in vitro and inhibits growth of human tumors in immune-deficient and immune-reconstituted SCID-beige mice. Methods: A phase 1, dose-escalation study of CP-870,893 was designed to characterize the safety and maximum tolerated dose (MTD) of single doses of CP-870,893 in patients (pts) with advanced solid tumors. CP-870,893 was administered i.v. on day 1 and pts were followed for 43 days. Results: Twenty-nine pts received CP-870,893 in doses ranging from 0.01 to 0.3 mg/kg. Dose limiting toxicity was observed in 2 of 7 pts at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). The MTD was defined as 0.2 mg/kg. The most common adverse event was dose-related cytokine release syndrome (grade 1 to 2). Abnormal lab findings included dose-related and transient elevations in liver transaminases (grade 1 to 2; one pt with grade 3). Modest elevations in serum D-dimer were observed in pts treated at the highest dose levels. Four pts with melanoma (14% of all pts and 27% of pts with melanoma) had objective partial responses (PR) at day 43 evaluation (one PR sustained at 7+ months and 3 unsustained on follow-up scans). Each pt with a PR received 0.2 or 0.3 mg/kg of antibody. To assess pharmacodynamic actions of CP-870,893, flow cytometry was performed on peripheral blood B cells, which uniformly express CD40. CP-870,893 infusion resulted in depletion of peripheral CD19+ B cells (>80% depletion at the highest dose levels). Among B cells remaining in blood, we found a marked, dose-related upregulation of costimulatory and MHC molecules after treatment. Conclusions: Clinical and laboratory findings demonstrate biological activity of CP-870,893. Antitumor activity was observed in 4 pts with melanoma. Further studies of repeated doses of CP-870,893, and CP-870,893 in combination with other antineoplastic agents, are warranted. [Table: see text]

Clinical Activity and Immune Modulation in Cancer Patients Treated With CP-870,893, a Novel CD40 Agonist Monoclonal Antibody

2007 ◽  
Vol 25 (7) ◽  
pp. 876-883 ◽  
Author(s):  
Robert H. Vonderheide ◽  
Keith T. Flaherty ◽  
Magi Khalil ◽  
Molly S. Stumacher ◽  
David L. Bajor ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Solid Tumors ◽  
Immune Modulation ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Biologically Active ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Cell Surface Molecule

PurposeThe cell-surface molecule CD40 activates antigen-presenting cells and enhances immune responses. CD40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective CD40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study.Patients and MethodsPatients with advanced solid tumors received single doses of CP-870,893 intravenously. The primary objective was to determine safety and the maximum-tolerated dose (MTD). Secondary objectives included assessment of immune modulation and tumor response.ResultsTwenty-nine patients received CP-870,893 in doses from 0.01 to 0.3 mg/kg. Dose-limiting toxicity was observed in two of seven patients at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). MTD was estimated as 0.2 mg/kg. The most common adverse event was cytokine release syndrome (grade 1 to 2) which included chills, rigors, and fever. Transient laboratory abnormalities affecting lymphocytes, monocytes, platelets, D-dimer and liver function tests were observed 24 to 48 hours after infusion. Four patients with melanoma (14% of all patients and 27% of melanoma patients) had objective partial responses at restaging (day 43). CP-870,893 infusion resulted in transient depletion of CD19+ B cells in blood (93% depletion at the MTD for < 1 week). Among B cells remaining in blood, we found a dose-related upregulation of costimulatory molecules after treatment.ConclusionThe CD40 agonist mAb CP-870,893 was well tolerated and biologically active, and was associated with antitumor activity. Further studies of repeated doses of CP-870,893 alone and in combination with other antineoplastic agents are warranted.

scholarly journals Monoclonal Antibody-Based Immunotherapy and Its Role in the Development of Cardiac Toxicity

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 86
Author(s):  
Mohit Kumar ◽  
Chellappagounder Thangavel ◽  
Richard C. Becker ◽  
Sakthivel Sadayappan
Keyword(s):  
Cancer Patients ◽  
Immune Modulation ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Induced Pluripotent Stem Cell ◽  
High Volume ◽  
Oncolytic Viruses ◽  
Model Systems ◽  
Volume Data ◽  
Late Cardiotoxicity

Immunotherapy is one of the most effective therapeutic options for cancer patients. Five specific classes of immunotherapies, which includes cell-based chimeric antigenic receptor T-cells, checkpoint inhibitors, cancer vaccines, antibody-based targeted therapies, and oncolytic viruses. Immunotherapies can improve survival rates among cancer patients. At the same time, however, they can cause inflammation and promote adverse cardiac immune modulation and cardiac failure among some cancer patients as late as five to ten years following immunotherapy. In this review, we discuss cardiotoxicity associated with immunotherapy. We also propose using human-induced pluripotent stem cell-derived cardiomyocytes/ cardiac-stromal progenitor cells and cardiac organoid cultures as innovative experimental model systems to (1) mimic clinical treatment, resulting in reproducible data, and (2) promote the identification of immunotherapy-induced biomarkers of both early and late cardiotoxicity. Finally, we introduce the integration of omics-derived high-volume data and cardiac biology as a pathway toward the discovery of new and efficient non-toxic immunotherapy.

scholarly journals P32-5 Eosinophilia predicted longer survival for solid tumor cancer patients treated with anti-PD-1 monoclonal antibody

2021 ◽  
Vol 32 ◽  
pp. S350
Author(s):  
Kazuhito Suzuki ◽  
Kaichi Nishiwaki ◽  
Jun Miki ◽  
Naoto Takahashi ◽  
Makoto Odaka ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cancer Patients ◽  
Solid Tumor

PHASE I TRIAL OF MURINE ANTI-GANGLIOSIDE (GD2) MONOCLONAL ANTIBODY (Mab) 14G2A IN CANCER PATIENTS

1992 ◽  
Vol 11 (2) ◽  
pp. 135 ◽  
Author(s):  
J. L. Murray ◽  
J. E. Cunningham ◽  
H. M. Brewer ◽  
M. H. Janus ◽  
D. A. Podoloff ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Cancer Patients ◽  
Phase I Trial ◽  
Ganglioside Gd2

BEGONIA: Phase 1b/2, open-label, platform study of the safety and efficacy of durvalumab (D) ± paclitaxel (P) with novel oncology therapies for first-line metastatic triple-negative breast cancer (mTNBC): Addition of arm 7, D + datopotamab deruxtecan (Dato-DXd; DS-1062).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1105-TPS1105
Author(s):  
Peter Schmid ◽  
Ana Tablante Nunes ◽  
Hannah Dry ◽  
Rachel Dougherty ◽  
Vatsala Karwe ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Primary Endpoint ◽  
Topoisomerase I ◽  
Objective Response ◽  
Locally Advanced ◽  
Clinical Activity ◽  
First Line ◽  
Safety And Efficacy ◽  
Topoisomerase I Inhibitor ◽  
Heavily Pretreated

TPS1105 Background: Patients (pts) with mTNBC have limited treatment options and poor prognosis. The combination of immune checkpoint inhibitors with chemotherapy shows promise, but only a subset of pts with mTNBC derive benefit, highlighting the need for new combinations. BEGONIA is an ongoing Simon 2-stage, multicenter, multi-arm platform study evaluating the safety and efficacy of D, an anti–PD-L1 monoclonal antibody, with or without P, in combination with novel oncology therapies as first-line treatment for mTNBC (NCT03742102). Dato-DXd is an antibody-drug conjugate (ADC) consisting of a humanized anti-trophoblast cell surface antigen 2 (TROP2) IgG1 monoclonal antibody, a stable tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload. Dato-DXd displayed encouraging clinical activity with a manageable safety profile in heavily pretreated pts with metastatic NSCLC in the phase 1 TROPION-PanTumor01 (NCT03401385) study. TROP2 is highly expressed on breast and other epithelial tumors, and a TROP2 ADC showed activity in heavily pretreated pts with mTNBC (Bardia, NEJM 2019). Methods: Eligible female pts are aged ≥18 years with untreated unresectable, locally advanced or mTNBC, ≥12 months since prior taxane therapy, ECOG PS 0/1, adequate organ function, and ≥1 nonirradiated measurable lesion. For Arm 7, pts are excluded if they have clinically significant corneal disease, history of interstitial lung disease/pneumonitis, underlying pulmonary disorder, or prior treatment with an ADC containing a topoisomerase I inhibitor. Arm 7 will evaluate D (1120 mg) + Dato-DXd (6 mg/kg) given intravenously every 3 weeks until disease progression or unacceptable toxicity. Part 1 of each arm includes a total of 30 pts with a safety run-in (n=6) to observe dose-limiting toxicities, identify the recommended phase 2 dose (RP2D), and detect an efficacy signal for part 1 expansion. The primary endpoint of part 1 is safety and tolerability. Secondary endpoints include investigator-assessed objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Once the RP2D has been established for part 1, a futility analysis will be performed with an option to expand the cohort to an additional 27 pts if expansion criteria are met. The primary endpoint for part 1 is ORR. Tumors will be assessed every 6 weeks per RECIST v1.1. Kaplan-Meier analysis will be used for PFS and OS. PD-L1 and TROP2 expression will be assessed by immunohistochemistry. Enrollment is ongoing. Clinical trial information: NCT03742102 .

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