Phase 1b study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTEimmune-oncology therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5100-TPS5100
Author(s):  
Rahul Raj Aggarwal ◽  
Ana Aparicio ◽  
Axel Heidenreich ◽  
Shahneen Kaur Sandhu ◽  
Yiran Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
De Novo ◽  
Objective Response ◽  
Human Study ◽  
Histological Transformation ◽  
Phase 1B

TPS5100 Background: NEPC is an aggressive cancer with poor prognosis. No standard treatment approach for NEPC exists and it remains an unmet need. NEPC is usually treatment-emergent, characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor (NET), and may develop in 15%–20% of patients (pts) treated with standard prostate adenocarcinoma therapies, including novel hormonal therapies. The inhibitory Notch ligand, Delta-like ligand 3 (DLL3), is highly expressed on the surface of cancer cells, including NEPC cells, making it an attractive and a promising therapeutic target. AMG 757 is an HLE BiTE immuno-oncology therapy designed to redirect cytotoxic T cells to tumor cells by binding DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. AMG 757 showed in vitro activity in DLL3-expressing NETs, including NEPC. Preliminary results of an on-going first-in-human study suggest AMG 757 is safe and effective in pts with small cell lung cancer (NCT03319940), which prompted its study in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating AMG 757 infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with NEPC whose disease progressed/recurred after ≥1 treatment course including a platinum-based regimen for de novo NEPC or an androgen signaling inhibitor, measurable disease per modified RECIST 1.1 per Prostate Cancer Working Group 3 modifications, ECOG performance status ≤2, life expectancy > 3 mo, adequate organ function, and no untreated/symptomatic brain metastases. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757. Secondary objectives are to evaluate antitumor activity (ie, objective response, duration of response, progression-free survival, overall response) and characterize pharmacokinetics. The starting dose for dose exploration will be based on the dose deemed safe and tolerable in the ongoing trial of AMG 757 in SCLC. The study is open to enrollment. Clinical trial information: NCT04702737.

Differentiated activity profile for the PD-1 inhibitor balstilimab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5529-5529
Author(s):  
Cailin Joyce ◽  
Dhan Chand ◽  
Benjamin Duckless ◽  
Manuel Hidalgo ◽  
Joseph Elan Grossman ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Culture System ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Activity Profile ◽  
Double Positive ◽  
Programmed Death

5529 Background: The development and clinical application of immune checkpoint inhibitors has transformed the therapeutic landscape for cancer treatment in recent years. Balstilimab (AGEN2034) is a fully human, monoclonal IgG4 antibody that binds with high affinity to programmed death 1 (PD-1), thus preventing the interaction between this receptor and its ligands programmed death ligand 1 and 2 (PD-L1, PD-L2). Emerging evidence suggests that balstilimab exhibits a differentiated activity profile compared to currently approved anti-PD-1 agents, including pembrolizumab and nivolumab. Methods: Balstilimab as monotherapy was evaluated in a large phase 2 study in patients (pts) with recurrent/metastatic cervical cancer who had relapsed after a platinum-based treatment regimen for advanced disease. Pts were dosed at 3 mg/kg once every 2 weeks for up to 24 months and antitumor activity was assessed using RECIST v1.1. The tumor cell killing activity of balstilimab was evaluated preclinically in a human co-culture system of (1) primary T cells engineered to recognize NY-ESO-1 and (2) NY-ESO-1+ cancer cell lines, including PD-L1 and/or PD-L2-deficient engineered lines. The co-culture system was maintained for ̃ two weeks to drive partial T cell exhaustion; a state where cytotoxicity is compromised but recoverable with PD-1 blockade. Cytotoxicity of these partially exhausted T cells was quantified against PD-L1/L2 double positive, single positive, or double negative cancer cells in the presence or absence of PD-(L)1 antibodies. Results: In the second-line treatment setting for pts with advanced cervical cancer, balstilimab showed a numerically higher objective response rate (ORR) in subjects with PD-L1+, squamous cell carcinoma (SCC) tumors (21%, 95% CI, 12.7-32.6%) than those reported for pembrolizumab. Unlike pembrolizumab, balstilimab showed activity in PD-L1(-) pts, and irrespective of tumor histology (ORR 7.9%, 95% CI, 2.7-20.8%). Despite lower overall PD-L1 positivity compared to SCC (41.7 v 72.9%), an ORR of 12.5% (95% CI, 5.9-24.7%) was observed in the subset of pts with a poorer prognosis, those with cervical adenocarcinoma. Concordant with clinical observations, balstilimab demonstrated superior rescue of antigen-specific T cell cytotoxicity in vitro relative to pembrolizumab, nivolumab, or atezolizumab. Balstilimab also induced cytotoxicity against PD-L1 and/or PD-L2 deficient target cancer cells. Conclusions: Taken together, these data suggest functional differentiation of balstilimab from other PD-1 inhibitors with potentially important implications for extending the therapeutic reach of anti-PD-1 therapy. Investigation of the underlying mechanistic basis for these findings is ongoing. Clinical trial information: NCT03104699.

Efficacy and safety of pegylated human IL-10 (AM0010) in combination with an anti-PD-1 in renal cell cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4567-4567
Author(s):  
Aung Naing ◽  
Jeffrey R. Infante ◽  
Deborah Jean Lee Wong ◽  
Wolfgang Michael Korn ◽  
Raid Aljumaily ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
De Novo ◽  
Cell Cancer ◽  
Objective Response ◽  
Endocrine Disorders ◽  
Efficacy And Safety

4567 Background: IL-10 has anti-inflammatory activity and stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are expressed on activated CD8 T cells, providing a rationale for combining AM0010 and an anti-PD1. The efficacy and safety profile for AM0010 alone was established in poor to intermediate risk RCC pts treated in 3rdLOT. Objective responses were observed in 4 of 15 pts with RCC. In the dose escalation of AM0010 plus pembrolizumab, 4 of 8 patients had an objective response. The mPFS was 16.7 months and the mOS has not been reached, median follow up (mFU) is 19.3 mo. Methods: In this Phase 1b, 29 pts. with metastatic RCC were enrolled until Nov. 18 2016 on AM0010 (10 ug/kg daily SC) and nivolumab (3mg/kg, q2wk IV). 2 had favorable, 20 had intermediate and 4 had poor IMDC risk (3 were not available). Pts. had a median of 1 prior therapy (range 1-3). All pts. had received a VEGFR-TKI. Tumor responses were assessed with irRC. Immune responses were evaluated by serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Results: AMO010 plus nivolumab was well tolerated. TrAEs were reversible. There were no autoimmune colitis, pneumonitis, or endocrine disorders. 14 patients had at least 1 G3/4 TrAE, including anemia (9), thrombocytopenia (5), hypertriglyceridaemia (4). 2 pts had a reversible cytokine release syndrome with splenomegaly and increased immune mediated red blood cell phagocytosis most likely precipitated by T-cell activation, as both pts had tumor responses. As of Jan 31 2017, partial responses (PR) were observed in 8 of 26 evaluable pts (31%). An additional 13 of 26 pts had stable disease (41%), 7 pts had tumor reductions of more than 30%. The mPFS and mOS has not been reached with a mFU of 5.2 mo. (range 0.3-10.3). AM0010 + anti-PD1 increased Th1 cytokines in the serum while decreasing TGFb, an expansion of proliferating PD1+ Lag3+ activated CD8 T cells and de-novo oligoclonal expansion of T cell clones in the blood. Conclusions: AM0010 in combination with nivolumab is well-tolerated in RCC pts. The efficacy and the observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with nivolumab. Clinical trial information: NCT02009449.

A CD19/CD3 Bispecific Tandab, AFM11, Recruits T Cells To Potently and Safely Kill CD19+ Tumor Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4405-4405
Author(s):  
Eugene Zhukovsky ◽  
Uwe Reusch ◽  
Carmen Burkhardt ◽  
Stefan Knackmuss ◽  
Ivica Fucek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Cross Reactivity ◽  
Equity Ownership

Abstract To harness the potent tumor-killing capacity of T cells for the treatment of CD19+ malignancies, we developed a humanized bispecific tetravalent antibody, with two binding sites for CD3 and CD19, the CD19/CD3 RECRUIT-TandAb AFM11. CD19 is expressed from early B cell development through differentiation into plasma cells, and is an attractive alternative to CD20 as a target for the development of therapeutic antibodies to treat B cell malignancies such as Non Hodgkin Lymphoma. Since native antibodies cannot recruit T cells, we engineered a bispecific anti-CD19/anti-CD3 TandAb. The tumor-specific CD19 antigen module targets the TandAb to cancer cells, while simultaneously, the CD3 effector module recruits and activates T cells, leading to cancer cell lysis. The advantages of the TandAb technology, relative to other bi-functional fragment antibody scaffolds, include: improved pharmacokinetics (PK) enabling intravenous dosing, more drug-like properties, and avidity-enhanced efficacy for the targeting and killing of tumor cells. We evaluated in vitro efficacy and safety using CD19+ cell lines, and in vivo efficacy in a murine NOD/scid xenograft model reconstituted with human PBMC. Further, we used standard preclinical IND enabling assays to evaluate tissue cross reactivity, PK, and toxicological profile (local tolerance, hematocompatibility, effects on hematopoesis, etc). In vitro assays demonstrated the higher potency and efficacy of target cell lysis by AFM11 relative to a bispecific tandem scFv (that is currently in clinical evaluation). CD8+ T cells dominate early AFM11-mediated cytotoxicity (4 hrs) while after 24 hrs both CD4+ and CD8+ T cells equally contribute to tumor lysis with EC50 between 0.5 – 5 pM; cytotoxicity was independent of CD19 cell-surface density. AFM11 exhibited similar cytotoxicity over effector:target ratios ranging from 5:1 to 1:5, and facilitated serial T cell-killing of its targets. The advantage of AFM11 over the bispecific tandem scFv was most pronounced at lower effector:target ratios. AFM11 activated T cells only in the presence of CD19+ cells. In PBMC cultures, AFM11 induced CD69 and CD25 expression, T cell proliferation, and production of IFN-γ, TNF-α, IL-2, IL-6, and IL-10. Depletion of CD19+ cells from PBMC abrogated these effects, demonstrating that the T cell activation is strictly CD19+ target-dependent. Thus, AFM11 should not elicit the devastating cytokine release observed when full-length antibodies bind CD3. Up to one week co-incubation with AFM11 did not inhibit T cell cytotoxicity, suggesting that the TandAb does not induce anergy. In vivo, AFM11 induced dose-dependent growth inhibition of Raji tumors; a single 0.5 mg/kg dose exhibited efficacy similar to 5 daily injections. In the tissue cross reactivity study, only tissues containing CD19+ and CD3+ cells were stained by AFM11; all other tissues, including vital organs, displayed no cross reactivity. Similarly, no local intolerance was observed in rabbits, and no effect on myeloid and erythroid progenitors was observed in a colony-forming assay. Strong accumulation of 125I-labeled AFM11 was observed in the tumors of mice engrafted with CD19+ cancer cells, and no unspecific organ accumulation was observed. Finally, evaluated on the basis of Cmax and the area under the curve (AUC), AFM11 exhibited dose linearity (20 – 500 mg AFM11 dose range) upon single i.v. bolus administration in mice; half-life (T1/2) ranged from 18.4 to 22.9 hr. In summary, AFM11 is a highly efficacious novel drug candidate for the treatment of CD19+ malignancies with an advantageous safety profile and anticipated dosing regimen. Disclosures: Zhukovsky: Affimed Therapeutics AG: Employment, Equity Ownership. Reusch:Affimed Therapeutics AG: Employment. Burkhardt:Affimed Therapeutics AG: Employment. Knackmuss:Affimed Therapeutics AG: Employment. Fucek:Affimed Therapeutics AG: Employment. Eser:Affimed Therapeutics AG: Employment. McAleese:Affimed Therapeutics AG: Employment. Ellwanger:Affimed Therapeutics AG: Employment. Little:Affimed Therapeutics AG: Consultancy, Equity Ownership.

scholarly journals A First-in-Human Study of Autologous T Lymphocytes with Antibody-Dependent Cell Cytotoxicity (ADCC) in Patients with B-Cell Non-Hodgkin Lymphoma (NHL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3031-3031
Author(s):  
Michelle Poon ◽  
Yeh Ching Linn ◽  
Noriko Shimasaki ◽  
Lip Kun Tan ◽  
Liang Piu Koh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Human Study ◽  
B Cell Lymphoma ◽  
Grey Zone ◽  
Phase 1B ◽  
Equity Ownership

Abstract Recent trials in patients with B-cell malignancies have demonstrated the clinical potential of chimeric antigen receptor (CAR)-directed T cells. We developed a chimeric receptor (antibody-coupled T-cell receptor, ACTR) consisting of high affinity CD16 V158, CD8α transmembrane domain, 4-1BB and CD3ζ (Kudo et al. Cancer Res 2014). Expression of ACTR conferred ADCC capacity to T cells. In vitro and in immunodeficient mice, ACTR T cells specifically killed B-NHL and chronic lymphocytic leukemia cells tagged with the anti-CD20 antibody rituximab. Trastuzumab induced ACTR-mediated T cell killing of breast and gastric cancer cells, and anti-GD2 of neuroblastoma and osteosarcoma cells. Thus, infusion of ACTR T cells might significantly augment the anti-tumor potential of immunotherapeutic antibodies, and expand options for cell therapy of cancer. To assess the safety of this strategy and explore its efficacy, we began a pilot study in patients with relapsed/refractory CD20+ B-NHL (ATTCK20; ClinicalTrials.gov No. NCT02315118). In this first-in-human study, ACTR expression is achieved by mRNA electroporation and, hence, is transient. In Phase 1a, 3 subjects receive one dose of autologous ACTR T cells (0.5 x 106/kg) 2 days after rituximab (500 mg/m2); a second dose of ACTR T cells at 0.5 x 107/kg 28 days later is allowed if there is no toxicity and evidence of response. Interleukin-2 (IL-2) is given subcutaneously at 1 million IU/m2/d x 3 during the first week after infusion. Phase 1b plans up to 4 infusions of ACTR T cells (0.5 x 107/kg) at 10 day intervals, each preceded by rituximab at 375 mg/m2; IL-2 (as in Phase1a) is given after the first 2 infusions only. Six subjects have been enrolled to date (3 in Phase 1a, 3 in Phase 1b) and received a total of 14 ACTR T cell infusions. All had advanced CD20+ B-NHL (2 diffuse large B cell lymphoma, 2 primary mediastinal B cell lymphoma, 1 mantle cell lymphoma, and 1 mediastinal grey zone lymphoma) and had failed multiple lines of therapy. As a lymphodepleting regimen prior to the first ACTR T cell infusion, 5 of the 6 patients received fludarabine (25 mg/m2/d x 5) plus cyclophosphamide (60 mg/kg/d x 1, n=3; 900 mg/m2/d x 1, n=2); the remaining patient received bendamustine (90 mg/m2/d x 2). After leukapheresis, T cells were cultured under cGMP conditions with anti-CD3 and -CD28 antibodies, and IL-2. After 10 days, cells were electroporated with ACTR mRNA using the MaxCyte GT system. The next day, median ACTR expression in T cells, as shown by flow cytometry, was 95.8% (range, 82.8%-99.3%; n=14). With Rituximab, this produced a median cytotoxicity of 77.5% (67.6%-97.6%; n=14) against CD20+ Daudi cells at a 4:1 effector : target ratio in 4 hours. As expected, ACTR expression in vitro remained high for the first 3-4 days, declining thereafter. We met or exceeded the estimated minimum target levels of CD3+ ACTR+ cells in 13 of the 14 infused cell products. CD3+ ACTR+ cells (mostly CD8+) were detectable in peripheral blood 1 day after infusion and reached their peak on day 3-4 when they represented 0.43-11.20 (median, 1.27) cells per µL. They became undetectable after day 6, reflecting the kinetics of ACTR expression in vitro. As of July 2016, 5 of the 6 patients are evaluable, with a median follow-up of 60 weeks (range, 6-83) after the last ACTR-T cell infusion; the remaining patient has received 3 of the 4 scheduled cycles. The main toxicities were grade 3-4 cytopenias: these were observed in all patients and likely due to the lymphodepleting regimen. There was no non-hematologic toxicity, nor evidence of cytokine release syndrome. In Phase 1a, 2 patients had progressive disease (PD) and 1 had stable disease (SD) on CT scan following the first and second infusions, with PET-CT showing reduced FDG avidity and central areas of photopenia suggestive of necrosis. Of the 2 Phase 1b patients evaluable for response, 1 had PD after the third infusion and was taken off study; the other had SD 1 month after 4 ACTR-T infusions; the 2nd month assessment was interpreted as PD. The initial results of this ongoing trial using autologous T cells with transient ACTR expression are encouraging and warrant additional studies with more potent formulations of this technology. To this end, a clinical trial for patients with relapsed/refractory CD20+ B-NHL in which ACTR is permanently expressed in autologous T cells via viral vector transduction is planned (ClinicalTrials.gov No. NCT02776813). Disclosures Campana: Unum Therapeutics: Consultancy, Equity Ownership, Patents & Royalties; Juno Therapeutics: Patents & Royalties; Nkarta Therapeutics: Consultancy, Equity Ownership, Patents & Royalties.

Expression of Functional B7-H1 Molecules on Blasts from Myelodysplastic Syndromes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2429-2429
Author(s):  
Asaka Kondo ◽  
Taishi Yamashita ◽  
Hideto Tamura ◽  
Chikako Sato ◽  
Risa Jo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Cell Lines ◽  
Myelodysplastic Syndromes ◽  
De Novo ◽  
Early Stage ◽  
Interferon Γ ◽  
Refractory Anemia ◽  
Cd34 Cells

Abstract B7-H1 (CD274) is a costimulatory/coinhibitory molecule that plays a crucial role in T cell regulation in various immune responses. B7-H1 expression is detected not only on professional antigen-presenting cells but also on some tumor cells. It has been reported that B7-H1 molecules on tumor cells are associated with poor prognosis in patients with some tumors such as renal cancer and breast cancer. We reported previously that B7-H1 expression on blasts is rare in de novo acute myeloid leukemia (AML) (Clin Cancer Res, 2003). In this study, we investigated whether functional B7-H1 molecules are expressed on blasts from myelodysplastic syndromes (MDS). Using flow cytometry (FCM), we analyzed B7-H1 expression in MDS cell lines (OIH-1, SKM-1, and F36P) and on blasts in bone marrow (BM) or peripheral blood samples. These samples were obtained from 40 MDS patients and 19 patients with AML transformed from MDS (AL-MDS). Among the cell lines, F36P cells showed a high level of B7-H1 expression. In patient samples, the percentage of B7-H1+ blasts tended to be the highest in patients with AL-MDS, followed by refractory anemia with excess of blasts (RAEB) in transformation (RAEB-t) and RA/RAEB (P<0.1). B7-H1+ cases, defined as samples in which more than 5% of blasts expressed B7-H1 (5% was the highest value of B7-H1 expression in normal CD34+ cells in our study), were observed in 0/13, 5/15 (33.3%), and 6/12 (50%) patients in the RA, RAEB, and RAEB-t categories, respectively. B7-H1 expression in MDS cell lines and on MDS patient blasts was induced or enhanced by cultivating cells with interferon-γ (IFNγ) or tumor necrosis factor-α (TNFα), which may be involved in the pathogenesis of MDS. The positive effect of the cytokines on B7-H1 expression was also observed in normal CD34+ cells. The combination of IFNγ and TNFα synergistically enhanced B7-H1 expression not only in MDS cell lines and on MDS patient blasts but also in normal CD34+ cells. Next, to investigate the features of B7-H1+ MDS blasts, cell cycle was determined using FCM. The percentages of cells in G0/G1 phase were lower and those in G2/M phase were higher in B7-H1+ F36P cells compared with B7-H1− F36P cells. The data were essentially the same for B7-H1+ and B7-H1− SKM-1 cells. To investigate the immunomodulatory effect of B7-H1+ blasts on T cells, we examined the proliferation and apoptosis of T cells cultured with irradiated B7-H1+ F36P cells. The addition of blocking antibodies to B7-H1 and its receptor PD-1 in this coculture increased the proliferation and decreased the apoptosis of CD4+ and CD8+ T cells, suggesting that B7-H1 on MDS blasts induces T-cell apoptosis. Taking the results together, in MDS: B7-H1 expression on blasts occurs more often in the advanced than in the early stage; B7-H1 expression on blasts may be induced by cytokines derived from the BM environment; B7-H1+ blasts cycle more actively than B7-H1− blasts; and B7-H1 molecules on blasts suppress T cells. These findings indicate that B7-H1 molecules on blasts may contribute to disease progression in MDS.

Phase 1b study with PEGylated human IL-10 (AM0010) with 5-FU and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 399-399 ◽  
Author(s):  
J. Randolph Hecht ◽  
Aung Naing ◽  
Gerald Falchook ◽  
Manish R. Patel ◽  
Jeffrey R. Infante ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
De Novo ◽  
Single Agent ◽  
Hematological Toxicity ◽  
Phase 1B

399 Background: The benefit of adding nal-irinotecan or oxaliplatin to 5-FU in second-line therapy for PDAC is relatively small and it has been refractory to immune therapies. The success and the durability of immunotherapy is thought to depend on the activation and expansion of intratumoral, tumor specific cytotoxic CD8+ T cells which are absent in most PDACs. AM0010 stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune stimulation and prolonged stable disease in PDAC patients (pts) with single agent AM0010 was recently presented. Irinotecan may eliminate cytotoxic T cells. Treatment with platinum or 5-FU may activate immune responses to cancer and AM0010 has synergistic anti-tumor function with both in preclinical models. In this phase 1b clinical study, the efficacy of AM0010 with FOLFOX was explored in patients with PDAC. Methods: PDAC pts progressing on a median of 1 prior therapy (range 1-3) were treated daily with AM0010 in combination with FOLFOX (n=20). Tumor responses were monitored using irRC. Immune responses were monitored using analysis of serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Pretreatment samples were analyzed by IHC for tumor infiltration by CD8+ T cells. Results: G3/4 TrAEs included thrombocytopenia (55%), anemia (45%) and neutropenia (25%). There was no significant bleeding or febrile neutropenia. 16 pts had a objective tumor response assessment; 2 had an irCR, 1 an irPR, 10 had irSD. Eight remain on treatment, 2 for > 1 year. ORR was 15%, the DCR was 65%. The mPFS was 3.9 months. AM0010 increased serum Th1 cytokines and reduced mediators of chronic inflammation IL-23 and IL-17 and the immunosuppressive cytokine TGFb. AM0010 increased the number and proliferation of PD1+ activated CD8+ T cells and induced de-novo oligoclonal expansion of T cell clones without affecting total lymphocyte counts. Conclusions: AM0010 with FOLFOX is well tolerated with moderate hematological toxicity in patients with PDAC. The observed immune activation including CD8+ T cell activation and prolonged objective responses are encouraging and will be explored in a phase 3 trial starting in 2016.

Phase I study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTE immune therapy) targeting DLL3, in patients with small cell lung cancer (SCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9080-TPS9080
Author(s):  
Taofeek Kunle Owonikoko ◽  
Hossein Borghaei ◽  
Stéphane Champiat ◽  
Luis G. Paz-Ares ◽  
Ramaswamy Govindan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Phase 1 ◽  
Immune Therapy ◽  
Platinum Based Chemotherapy

TPS9080 Background: SCLC is an aggressive neuroendocrine tumor with poor prognosis and few treatment options. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed on the surface of most SCLC tumors but minimally expressed in normal tissues. As such, DLL3 may be a promising therapeutic target. AMG 757 is an HLE BiTE immune therapy designed to redirect cytotoxic T cells to cancer cells by binding to DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In addition to its direct antitumor effect, BiTE immune therapy can inflame the tumor microenvironment. Combining AMG 757 with a PD-1 pathway inhibitor may lead to increased antitumor activity by enabling sustained T cell-dependent killing of tumor cells. Methods: NCT03319940 is an open-label, ascending, multiple-dose, phase 1 study evaluating AMG 757 as monotherapy; the protocol was recently amended to also evaluate AMG 757 in combination with pembrolizumab. The study will include a dose exploration (monotherapy and combination) followed by a dose expansion (monotherapy). Key eligibility criteria: adult patients with relapsed/refractory SCLC whose disease progressed or recurred after at least 1 platinum-based chemotherapy regimen, ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety/tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757 as monotherapy and in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and evaluate preliminary antitumor activity; exploratory objectives are to assess immunogenicity and changes in biomarkers in blood and tumor tissue. In the dose exploration phase, dose escalation/de-escalation decisions will be guided by a Bayesian logistic regression model; backfill enrollment at dose levels deemed safe and tolerable will be allowed. The study is open and recruiting patients. Clinical trial information: NCT03319940.

KITE-439: A phase I study of HPV16 E7 T cell receptor-engineered T cells in patients with relapsed/refractory HPV16-positive cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3149-TPS3149
Author(s):  
Kedar Kirtane ◽  
Erminia Massarelli ◽  
Glenn J. Hanna ◽  
Christopher Austin Klebanoff ◽  
George Blumenschein ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
T Cell ◽  
Head And Neck ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Primary Endpoint ◽  
Cell Receptor ◽  
Engineered T Cells ◽  
Phase 1B

TPS3149 Background: Human papillomavirus 16 (HPV16) is the most prominent subtype across invasive head and neck cancers, as well as cervical cancer and other anogenital cancers (Saraiya M, et al. J Natl Cancer Inst. 2015). The HPV16 E7 (E7) viral antigen is important for the survival of HPV-positive tumor cells but is absent from normal human tissue, making it an attractive target for anti-cancer therapy. Preclinical efficacy has been observed with MHC class I-restricted T cell receptor (TCR)-engineered T cells targeting E7 on HPV16-positive tumor cells (Jin BY, et al. JCI Insight. 2018). This Phase 1, first-in-human, open-label, multicenter study (NCT03912831) will evaluate the safety and efficacy of KITE-439, an autologous TCR-engineered T cell therapy targeting E7, in HLA-A*02:01–positive patients with relapsed/refractory HPV16-positive cancers. Methods: A single-patient dose-escalation schema will be used in Phase 1A of the study, enrolling up to 30 patients. Phase 1A will evaluate safety and inform the recommended dose of KITE-439 for Phase 1B. Approximately 45 patients with squamous cell cancer of the head and neck, cervical cancer, and other HPV16-positive tumors will be included in Phase 1B. Patients in Phase 1A and Phase 1B may receive optional bridging therapy followed by cyclophosphamide and fludarabine conditioning chemotherapy. Patients will then receive an infusion of KITE-439 at 1 × 106 up to 1 × 108 TCR-transduced T cells/kg along with daily subcutaneous IL-2 therapy for a maximum of 14 doses post-infusion. The primary endpoint for Phase 1A is the incidence of adverse events defined as dose-limiting toxicities. The primary endpoint for Phase 1B is investigator-assessed objective response rate per modified RECIST v1.1 criteria (Eisenhauer EA, et al. Eur J Cancer. 2009). Secondary endpoints for Phase 1B include duration of response, progression-free survival, overall survival, and safety. Patients ≥ 18 years must be HLA-A*02:01–positive and have relapsed/refractory HPV16-positive cancer, an ECOG PS of ≤ 1, and adequate bone marrow and organ function. Key exclusion criteria include a history of stroke, myocardial infarction, or symptomatic deep vein thrombosis/pulmonary embolism, known infection with human immunodeficiency virus, detectable hepatitis C, or detectable hepatitis B. This study is currently open and accruing patients. Clinical trial information: NCT03912831 .

A phase I/II study of REGN5678 (Anti-PSMAxCD28, a costimulatory bispecific antibody) with cemiplimab (anti-PD-1) in patients with metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5592-TPS5592
Author(s):  
Charles G. Drake ◽  
Jingsong Zhang ◽  
Mark N. Stein ◽  
Yuanfang Xu ◽  
Frank A. Seebach ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Tumor Antigen ◽  
Objective Response ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Anti Tumor Activity

TPS5592 Background: Bispecific antibodies (bsAbs) are emerging as a protein-based therapeutic strategy for directing T-cell-mediated cytotoxicity in a tumor antigen-specific manner, typically by binding to both tumor antigen and the CD3 receptor on T cells. REGN5678 is a human IgG4-based, first-in-class costimulatory bsAb designed to target prostate tumors by bridging prostate specific membrane antigen expressing tumor cells with the costimulatory receptor, CD28, on T cells, and providing amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor through the activation of CD28 signaling. At the tumor site, REGN5678 may synergize with PD-1 inhibitors. In mouse models, REGN5678 in combination with PD-1 antibody has improved anti-tumor activity compared with either therapy alone (Skokos et al CRI/CICON 2019; oral, session 3). This study evaluates the safety and anti-tumor activity of REGN5678 alone and in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after prior therapy. Methods: This is an open label, Phase I/II, first-in-human study evaluating safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of REGN5678 alone and in combination with cemiplimab in treatment-experienced mCRPC (NCT03972657). For inclusion, patients must have received at least two approved therapies for metastatic disease, including a second-generation hormonal agent. REGN5678 is administered weekly and cemiplimab (350 mg) is administered once every 3 weeks. During dose escalation, a 3-week safety lead-in of REGN5678 monotherapy will be administered prior to the addition of cemiplimab. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate safety, tolerability, and PK of REGN5678 alone and in combination with cemiplimab. Expansion cohort(s) will be enrolled once a REGN5678/cemiplimab recommended Phase II dose is determined. During the expansion phase, the primary trial objective is to assess clinical activity, as measured by objective response rate of REGN5678 in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. This study is currently open to enrollment. Clinical trial information: NCT03972657 .

scholarly journals P11.10 The IFNγ pathway mediates brain metastasis formation of breast cancer

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii44-iii44
Author(s):  
R Pedrosa ◽  
J M Kros ◽  
B Schrijver ◽  
R Marques ◽  
P Leenen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
T Cell Response ◽  
Activated T Cells

Abstract BACKGROUND In previous work we showed the prominence of the T-cell response in the formation of brain metastases of primary ER negative breast cancers (Mustafa et al, Acta Neuropathol 2018). We also showed that breast cancer cells co-cultured with stimulated T lymphocytes overexpress Guanylate-binding protein 1 (GBP1) accompanying increased trespassing ability through an in vitro blood-brain barrier (BBB) model. In addition, we demonstrated a predilection for metastasizing to brain of breast cancer cells that were co-cultured with activated T cells in a mouse model. We now scrutinize the importance of the IFNγ pathway for tresspassing of the tumor cells through the BBB following T cell contact. MATERIAL AND METHODS Anti-hIFN-γ-IgA antibodies were used to neutralize the IFNγ effects on the tumor cells. The effects on the tumor cells is only due to native IFNγ produced by activated T cells, not by recombinant IFNγ. Since the IFNγ expression itself enhances its expression by the T cells, we blocked IFNγ receptors prior to adding CD3+ T cell conditioned media to the breast cancer cells. The receptor blocking was achieved by antibodies to the IFNγα and IFNγβ subunits. Activation of the STAT1 pathway was monitored by GBP1 expression. For functional read-out the in vitro BBB model was used. RESULTS The presence of T-lymphocyte-secreted IFNγ in the primary breast cancer microenvironment activates the STAT1-dependent IFNγ pathway in breast cancer cells, endowing them with an increased ability to trespass the in vitro BBB. Moreover, direct inhibition of soluble IFNγ, or blocking of the IFNγ-specific receptor in breast cancer cells significantly decreases their ability to cross the BBB. CONCLUSION The results illustrate the specific action of T lymphocytes in the formation of cerebral metastasis involves the IFNγ signaling pathway as one of the crucial entangled pathways Subsequent studies should aim at the interference with the IFNγ pathway to develop preventive strategies against the formation of cerebral metastases of breast cancer.

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