scholarly journals 957 NKTR-255+cetuximab in patients with solid tumors: interim safety and efficacy results from the phase 1b dose-escalation study

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A1007-A1007
Author(s):  
Mehmet Altan ◽  
Amita Patnaik ◽  
Minal Barve ◽  
Lara Dunn ◽  
Patrick Cobb ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Fold Change ◽  
Biologically Active ◽  
Dose Escalation Study ◽  
Prior Therapy ◽  
Cytokine Analysis ◽  
Post Infusion ◽  
Phase 1B

BackgroundNKTR-255 is an investigational IL-15Rα-dependent, polymer-conjugated, recombinant human IL-15 agonist designed to provide sustained pharmacodynamic (PD) responses without the need for daily dosing. NKTR-255 engages all IL-15 receptor binding complexes to expand, proliferate and activate natural killer (NK) and CD8+ T-cells. This Phase 1b/2 trial (NCT04616196) evaluates NKTR-255+cetuximab in highly refractory patients with head-and-neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC).MethodsSuccessive cohorts received escalating doses of NKTR-255 (q3w) +cetuximab (250mg/m< sup >2</sup > weekly), 1 week after a loading dose of cetuximab alone. Safety (CTCAEv5.0; MTD/recommended Phase 2 dose [RP2D]) and efficacy (RECISTv1.1) were measured. PK/PD analyses were conducted, including assessment by flow cytometry/plasma cytokine analysis. Fold-change was calculated as treatment over baseline for NKTR-255 (baseline=1).ResultsAs of August 15, 2021, 12 patients had received ≥1 dose of NKTR-255+cetuximab; (37–70 years; 92% male; HNSCC n=4, CRC n=8; NKTR-255 1.5µg/kg n=7, NKTR-255 3.0µg/kg n=5). Patients had received a median 3.5 lines of prior therapy for metastatic disease. 11 patients had no response to the most recent prior therapy. Of the 12 patients, seven remain on treatment, with five not yet reaching first scan. RP2D has not yet been reached; dose escalation is ongoing.10 patients experienced an AE; one G5 AE occurred (due to progression). Seven patients reported NKTR-255-related AEs (all G1-2, except one G3 [which resolved in 24 hours]). Any-cause AEs in ≥20% were acneiform dermatitis, fatigue, and infusion-related reaction.Treatment-induced transient changes in inflammatory cytokines, including IFNy, MCP-1 and IL-6, at 1.5µg/kg (n=3) peaked 4 hours post-infusion and resolved by 24-48 hours. Mean T1/2 of NKTR-255 (1.5µg/kg dose, first cycle) was 27.8 hours.Dose-dependent expansion of NK and CD8+ T-cells was observed in peripheral blood. For NK cells, mean peak fold-change was ~4-fold and ~6-fold, and for CD8+ T-cells was ~2-fold and ~3-fold (1.5µg/kg and 3µg/kg dose levels, respectively). NK and CD8+ T-cells demonstrated increased Ki67+ proliferative ability.As of August 15, four patients in the 1.5µg/kg NKTR-255 dose cohort were response-evaluable: one CRC patient (4 prior metastatic treatment lines) reported a confirmed PR (–52%) after 3 cycles; two HNSCC patients reported SD.ConclusionsNKTR-255 was biologically active and led to expansion and proliferation of NK and CD8+ T-cells. Early dose-escalation data suggest that NKTR-255+cetuximab is safe and tolerable with preliminary anti-tumor activity. Updated data will be presented. NKTR-255, alone and in combination with daratumumab and rituximab, is also being evaluated in liquid tumors.AcknowledgementsThe authors thank the patients and their families involved in the trial.Trial RegistrationNCT04616196Ethics ApprovalThe study was approved by site IRBs.ConsentN/A

scholarly journals EPCT-24 THE REMIND TRIAL: MULTI-ANTIGEN TARGETED T CELLS FOR PEDIATRIC CNS TUMORS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i52-i52
Author(s):  
Melanie Grant ◽  
Maria Fortiz ◽  
Lu Wang ◽  
Haili Lang ◽  
Anushree Datar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dose Escalation ◽  
Autologous Tumor ◽  
Immunologic Response ◽  
Dose Escalation Study ◽  
Post Infusion ◽  
Ifn Γ ◽  
Group B ◽  
Cns Malignancies

Abstract Background Patients with relapsed CNS malignancies or DIPG face terrible prognoses. We hypothesized that T cells specific for 3 tumor-associated antigens (TAA), WT1, PRAME and survivin, would be safe and elicit anti-tumor immunity. Methods Patients (n=18) received autologous tumor antigen-associated T cells (TAAT) (up to 8x107/m2) for newly diagnosed DIPG (Group A) or recurrent CNS malignancies (Group B) on a Phase I dose-escalation study (NCT03652545) and were monitored for safety and response. Results/Discussion 16/18 patients who received TAAT completed the 45-day safety monitoring phase with no dose-limiting toxicities. Adverse events were minimal despite multiple pretreatments in Group B. Infused cells were predominantly CD3+ T cells (median 96%; range: 87–99%), with CD4+ and CD8+ comprising 16% (range: 5–87%) and 40% (range: 4–67%) respectively. Specificity for 1–3 TAAs was demonstrated in 11/18 TAAT by a-IFN-γ ELISPOT. Dose escalation is complete, and clinical and immunologic response assessments are ongoing. Plasma cytokine and proteomic analyses demonstrated dynamic post-infusion immune cytokine and protein responses. Consistent with an infusion-mediated immune response all patients in Grp A showed increased T cell effector, inflammatory and immune-stimulatory cytokines IFN-γ, TNF-α, IL-2, IL-5, IL-7, IL-1β, IL-6, IL-8, IL-12p70, IL-17A and GM-CSF at Weeks 1 and 2 post-infusion (n = 6). Of 9 patients who have been tested, 29/92 plasma proteins showed significant differences between dose levels 1 and 2, including increased IL-7 (p &lt;0.0004) and CD40L (p &lt;0.046) and reduced IL-4 (p &lt;0.0004). T cell receptor sequencing showed expansion and persistence of clones detected in infusion products. In summary, TAAT have thus far been safe and elicit immune responses in vivo. Clinical and immunologic response assessments are ongoing.

A phase Ia/Ib dose-escalation study of intravenously administered SB 11285 alone and in combination with nivolumab in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3162-TPS3162
Author(s):  
Filip Janku ◽  
James Strauss ◽  
Raghad Karim ◽  
Anthony J. Olszanski ◽  
Jason J. Luke ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Expression Patterns ◽  
Phase 2 ◽  
Tumor Cell Death ◽  
Dose Escalation Study ◽  
Pharmacodynamic Profile ◽  
Sting Pathway

TPS3162 Background: Activation of the Stimulator of Interferon Genes (STING) pathway in immune cells in the tumor microenvironment (TME) and tumor cells results in the induction of innate and adaptive immunity and subsequent activation of cytotoxic T cells and NK cells for durable anti-tumor responses. SB 11285 is a novel agonist of the STING pathway leading to the activation of tumor-resident APCs and priming of tumor antigen specific CD8+ T cells. In our preclinical studies using multiple tumor-derived cell lines, SB 11285 has been observed to cause the induction of cytokines, such as INF-b, INF- a, TNFa and others consistent with engagement of the STING target, as well as tumor cell death by STING-mediated apoptosis. SB 11285 reduced tumor volumes in multiple rodent tumor models when administered intravenously, intraperitoneally or intratumorally as monotherapy or in combination with checkpoint inhibitors such as anti-CTLA-4 or anti-PD-1 antibody. Systemic administration could additionally facilitate trafficking of newly activated CD8+T cells from periphery into the tumor site. Methods: This open-label, multicenter phase 1a/1b clinical trial (NCT04096638) aims to enroll approximately 110 patients in the dose escalation (Part 1) and expansion cohorts (Part 2). Part 1 of the trial is a dose escalation study with IV SB 11285 monotherapy followed by combination with the checkpoint inhibitor nivolumab. Part 1 Dose Escalation of the study will evaluate ascending doses of intravenously administered SB 11285 with respect to dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and the pharmacokinetic (PK)/pharmacodynamic profile as monotherapy and in combination with nivolumab. SB 11285, with a starting dose of 0.3μg/kg, will be administered as monotherapy weekly on Days 1, 8, 15, and 22 of repeated 28-day cycles in escalating doses and in combination with nivolumab administered on Q4W schedule. Part 2 Expansion Cohorts of the study will explore initial signs of efficacy in pre-specified tumor types (such as Melanoma, Head and Neck squamous cell carcinoma) using the recommended phase 2 dose (RP2D) of SB 11285 in combination with nivolumab. In addition, the biological effects of SB 11285 will be evaluated by changes in immune cell types and activation state, serum cytokines, and gene expression patterns indicative of activation of the immune compartment. The trial is being conducted at multiple sites in the U.S . Clinical trial information: NCT04096638 .

scholarly journals P01.01 A Phase 1a/1b dose-escalation study of intravenously administered SB 11285 alone and in combination with nivolumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A7.2-A8
Author(s):  
A ABBAS ◽  
J Strauss ◽  
F Janku ◽  
R Karim ◽  
A Olszanski ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Advisory Board ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Multiple Tumor ◽  
Part Time ◽  
Sting Pathway ◽  
Tumor Types

BackgroundImmunotherapy has emerged as a transformative approach for the treatment of cancer. However, a significant percentage of patients are nonresponsive to these immunotherapies or experience disease relapse which highlights the need for new therapies. Recent work has highlighted a major role for Stimulator of Interferon Genes (STING) agonists in immunotherapy. Conceptually, the activation of the STING pathway in immune cells in the tumor microenvironment (TME) and tumor cells could result in the induction of innate and adaptive immunity and subsequent activation of cytotoxic T cells and NK cells for durable anti-tumor responses. SB 11285 is a novel agonist of STING pathway leading to the activation of tumor-resident APCs and priming of tumor antigen specific CD8+ T cells. In our preclinical studies using multiple tumor-derived cell lines, SB 11285 has been observed to cause the induction of cytokines, such as INF-b, INF-a, TNFa and others consistent with engagement of the STING target, as well as tumor cell death by STING-mediated apoptosis. SB 11285 reduced tumor volumes in multiple rodent tumor models when administered intravenously, intraperitoneally and intratumorally. Systemic administration could additionally facilitate trafficking of newly activated CD8+T cells from periphery into the tumor site. In addition, preclinical models indicate that survival and local tumor shrinkage were significantly enhanced when SB11285 was administered with anti-CTLA-4 or anti-PD-1 antibody, suggesting that SB 11285 can be administered with anti-PD-1 and anti-CTLA-4 antibody for synergistic activity. A multiple ascending dose, phase 1a/1b trial of SB11285 in multiple tumor types has been initiated and the objectives of this trial include determining a safe and efficacious dose of intravenous SB 11285 and a preliminary assessment of antitumor activity/efficacy as either monotherapy or in combination with nivolumab.Materials and MethodsThis open-label, multicenter phase 1a/1b clinical trial (NCT04096638) aims to enroll approximately 110 patients in the dose escalation (Part 1) and expansion cohorts (Part 2). Part 1 of the trial is a dose escalation study with IV SB11285 monotherapy followed by combination with the checkpoint inhibitor nivolumab. Part 1 Dose Escalation of the study will evaluate ascending doses of intravenously administered SB 11285 with respect to dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and the pharmacokinetic (PK)/pharmacodynamic profile as monotherapy and in combination with nivolumab. SB 11285, with a starting dose of 0.3 μg/kg, will be administered as monotherapy weekly on Days 1, 8, 15, and 22 of repeated 28-day cycles in escalating doses and in combination with nivolumab administered on Q4W schedule. Part 2 Expansion Cohorts of the study will explore initial signs of efficacy in pre-specified tumor types (such as Melanoma, HNSCC) using the recommended phase 2 dose (RP2D) of SB 11285 in combination with nivolumab. In addition, the biological effects of SB 11285 will be evaluated by changes in immune cell types and activation state, serum cytokines, and gene expression patterns indicative of activation of the immune compartment. The trial is being conducted at multiple sites in the U.S.Disclosure InformationA. Abbas: A. Employment (full or part-time); Modest; Spring Bank Pharmaceutical Inc. J. Strauss: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Abbvie, Abbott Laboratories, Bristol-Myers Squibb, Intuitive Surgical, Johnson & Johnson, Merck. F. Consultant/Advisory Board; Modest; Tempus. Other; Modest; Dialectic Therapeutics. F. Janku: None. R. Karim: None. A. Olszanski: F. Consultant/Advisory Board; Modest; Bristol Myers Squibb. J.J. Luke: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; All to institution for clinical trials unless noted) Abbvie, Bristol Myers Squibb, Medimmune, Necktar, Novartis, Merck, Leap, Incyte, Immunocore, Compugen, Corvus, Evil, Five Prime, Genentech, Immatic. F. Consultant/Advisory Board; Modest; Consultant:Akrevia, Algios, Array, Astellas,AstraZeneca, Bayer, Bristol Myers Squibb/Advisory Board:7 Hills, Actym, Alphamab Oncology, Mavu (now part of Abbvie), Pyxis, Spring Bank Pharma, Tempest. Other; Modest; Travel: Akrevia, Bayer, Bristol Myers Squibb, Reflexion, EMD Serono, Incyte, Janssen, Merck, Mersana, Novartis. K. Leach: A. Employment (full or part-time); Modest; Spring Bank Pharmaceuticals Inc. R. Iyer: A. Employment (full or part-time); Modest; Spring Bank Pharmaceuticals Inc.

Abstract PR06: Phase 1b dose-escalation study of trametinib (MEKi) plus palbociclib (CDK4/6i) in patients with advanced solid tumors

2015 ◽  
Author(s):  
Ryan J. Sullivan ◽  
Rodabe N. Amaria ◽  
Donald P. Lawrence ◽  
John Brennan ◽  
Cathie Leister ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Phase 1B

The Use of Autologous LMP2-Specific Cytotoxic T Lymphocytes (CTL) for the Treatment of Relapsed EBV-Positive Hodgkin Disease and Non-Hodgkin Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 773-773
Author(s):  
Catherine M. Bollard ◽  
Elizabeth Buza ◽  
Helen Huls ◽  
Teresita Lopez ◽  
Stephen Gottschalk ◽  
...  
Keyword(s):  
T Cells ◽  
Partial Response ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Progressive Disease ◽  
Residual Tumor ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma ◽  
Clinical Responses

Abstract EBV-associated Hodgkin’s Disease (HD) and some non-Hodgkins lymphoma (NHL) show type II latency expressing the subdominant EBV antigens EBNA1, LMP1 and LMP2, which may serve as targets for immunotherapy approaches. In previous studies, we used polyclonal EBV-specific CTL in patients with relapsed EBV +ve HD and saw 2 complete and 1 partial response in 11 patients. Analyses of EBV-CTL lines showed that small populations of T cells reactive against the tumor-associated antigen LMP2 were present in the majority of the infused lines, with some expansion in the peripheral blood following infusion. We therefore hypothesized that CTL specifically targeting LMP2 might have greater efficacy in these patients. LMP2-CTL were generated from 14 patients using Dendritic Cells for initial stimulations then Lymphoblastoid Cell Lines (LCL) both of which had been genetically modified to overexpress LMP2 by transduction with an Ad5f35LMP2 vector. Polyclonal LMP2-CTL lines recognized 1–7 (median 2) LMP2 epitopes, as determined using pentamers and overlapping LMP2 peptide pools in ELISPOT assays. A mean of 22.8% (5–42.1%) of CD8+ T cells bound HLA-restricted LMP2 pentamers, compared to a mean of 0.11% (0.01–0.24%) of LMP2-pentamer positive CD8+ T cells found in CTL generated with genetically unmodified LCL from the same patients. So far, 11 patients have been treated on this dose escalation study - 6 patients have been treated on dose level (DL)1 (2 doses of CTL at 2x107/m2/dose given 2 wks apart in the outpatient clinic), 4 patients on DL2 (2x107/m2 and 1x108/m2) and 1 patient on DL3 (1x108/m2 and 2x108/m2). No immediate toxicity was observed. After CTL infusion, an increase in the frequency of EBV +/- LMP2-specific T cells could be detected in the blood in 8/10 evaluated patients (range 2–17.6 fold). Five of 6 patients who received LMP2-CTL as adjuvant therapy post stem cell transplant or chemotherapy remain in remission up to 22mths post LMP2-CTL. 1 patient presented with progressive disease 8 wks post CTL therapy. Five patients had detectable disease at the time of CTL therapy of whom 1 had progressive disease 8 wks post CTL and 4 had clinical responses (1 very good partial response and 3 clinical or radiologic complete responses). One of these 3 patients was evaluated 7 wks after receiving CTLs, which were predominantly CD4+ve (91.6%). Biopsies showed minimal residual NHL cells with increased CD4+ve T cells compared to pre-CTL biopsy specimens. Imaging studies performed 1 wk later were negative for NHL. This patient received 2 extra doses of CTL (given 8 wks apart) and re-evaluations showed CR on PET and CT scans. Two other patients had stable disease 8 wks post LMP2-CTL. Both patients received 2 further doses of LMP2-CTL. One patient is without evidence of disease 12 months post CTL. The other patient had a complete radiological response. This patient had a supraclavicular lymph node resection, which showed selective accumulation of LMP2-tetramer +ve T cells (0.3% compared to 0.01% in the peripheral blood) with few residual tumor cells. Immunotherapy with autologous LMP2-CTL is therefore well tolerated in patients with relapsed EBV+ve HD/NHL and infused LMP2-CTL cells can accumulate at tumor sites and induce clinical responses.

A Phase 1 Dose-Escalation Study of the Novel Cell Cycle Active Agent SNS-595 in Advanced Leukemias.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1962-1962
Author(s):  
Jeffrey E. Lancet ◽  
Judith E. Karp ◽  
Nancy Havrilla ◽  
Ute Hoch ◽  
Jeffrey Silverman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Dose Escalation ◽  
Phase 1 ◽  
Active Agent ◽  
Complete Response ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Acute Leukemias ◽  
Prior Therapy

Abstract SNS-595 is a novel, cell cycle active cytotoxic naphthyridine analog that induces G2 arrest in a variety of preclinical tumor models. We initiated an escalating-dose phase 1 trial of SNS-595, administered as a weekly x 3 (arm A) or twice weekly x 2 bolus (arm B), in patients with advanced or refractory acute leukemias. Objectives: The primary objectives were to:establish safety, tolerability, and MTD of SNS-595 given on each schedule,characterize pharmacokinetics (PK) of SNS-595 when given on these schedules. Secondary objectives were:assessment of clinical activity,exploration of potential biomarkers. Methods: SNS-595 was administered as a slow IV push on days 1, 8, 15 (arm A) or days 1, 4, 8, 11 (arm B). Minimum cycle length was 42 days (arm A) and 39 days (arm B). Additional cycles were permitted if patients achieved stable disease or better. The starting dose was 18 mg/m2/d on arm A, and 9 mg/m2/d on arm B and escalated by cohort using a modified Fibonacci schema. PK analyses for SNS-595 were performed on plasma samples collected during cycle 1. Pretreatment peripheral blood and bone marrow aspirate samples were collected for exploratory analyses of the level and functional activity of the DNA damage repair proteins DNA-PK and MSH2. Results: To date, 21 patients have been enrolled and are evaluable in the live database, including 13 patients assigned to arm A and 8 assigned to arm B, 12 males and 9 females with a median age of 64 years. Diagnoses included AML (19 patients) and ALL (2 patients). All patients had disease refractory to or relapsed from prior therapy (median 3 prior regimens (range 1–6)). Dose escalation has proceeded to 50 mg/m2/d (arm A) and 19 mg/m2/d (arm B). No dose-limiting toxicities have been observed to date. Non-dose limiting toxicities included nausea/vomiting, diarrhea, and mucositis . Grade 4 neutropenic fever was observed in only one patient. Plasma exposures at the first two dose levels in each arm increased linearly, resulting in AUCs of 5.5 – 17.8 ughr/mL for 9–27 mg/m2 doses. CL, Vss, and terminal half-lives were similar to those reported previously in solid tumor patients, and averaged ~2 L/hr/m2, 58 L/m2, and 23 hr, respectively. No patients have achieved complete response to date, although 6 patients (distributed across all dosing groups) experienced >50% reductions in peripheral blasts following cycle 1. Conclusion: SNS-595 appears to be well-tolerated in patients with advanced leukemias, with preliminary and promising signs of clinical activity as measured by decreases in leukemic blasts. Bone marrow ablation has not yet been achieved; patient accrual and dose-escalation are ongoing.

T Cell Responses during Long-Term Continuous Infusion of MT103 (MEDI-538; Anti-CD19 BiTE) in Patients with Relapsed B-NHL: Data from Dose-Escalation Study MT103-104.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2725-2725 ◽  
Author(s):  
Matthias Klinger ◽  
Peter Kufer ◽  
Petra Kirchinger ◽  
Ralf Lutterbüse ◽  
Eugen Leo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Cell Expansion ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Counts ◽  
T Cell Expansion

Abstract MT103 (MEDI-538) is a bispecific single-chain antibody construct directed at CD3 on human T cells and CD19 on human B lymphoma and normal B cells. Transient linkage of B and T cells by MT103 provides T cells with a T cell receptor (TCR)-like signal leading to redirected lysis of B cell targets without apparent need of costimulation and inducing T cells to proliferate, secrete cytokines and upregulate surface activation markers. TCR-like signalling by MT103 is strictly dependent on the presence of target cells. Redirected lysis of CD19-positive cells by MT103 is seen at low picomolar concentrations and at low effector-to-target ratios. The in-vivo half-life of MT103 is approximately two hours. In the ongoing dose escalation study MT103-104, patients with relapsed B-NHL have so far received continuous infusion of MT103 at maintenance flow-rates of 0.5, 1.5, 5 and 15 μg/m2/24h for 4 or 8 weeks following a 3+3 dose escalation design. Serum concentrations of MT103 remained constant over the entire treatment period at a level depending on the respective maintenance flow-rate. Depletion of circulating B (lymphoma) cells could be observed more frequently with increasing dose levels (DL) from DL1 to DL3, and in all evaluable patients at DL4. Three of six evaluable patients at DL4 showed clinical responses (2 PR, 1 CR) according to standardized Cheson criteria, but no patient of DL1-3. The time courses of absolute CD4 and CD8 T cell counts in peripheral blood were determined by flow cytometry. CD8 T lymphocytes were further subdivided for analysis into naïve T cells, TCM (central memory T cells), TEM (effector memory T cells) and TEMRA (non-proliferating terminally differentiated CTL), and CD4 T lymphocytes into naïve T cells, TCM and TEM. Activation of CD4 and CD8 T cell subsets was determined by measuring upregulation of CD69, CD25 and HLA-DR. Serum levels of cytokines were determined as additional biomarkers for T cell activation. In 50% of patients at DL1 to DL3, CD4 and CD8 T cell counts increased during the course of treatment - over pre-treatment levels. The TEM subset from both CD4 and CD8 T cells accounted for most of the observed increases, while the naïve T cell subsets showed no increase but also no signs of apoptosis. The non-proliferative TEMRA subset of CD8 T cells also remained unchanged in most patients. This indicated that the selective increase of proliferation-competent TEM subsets was attributed to MT103-induced T cell proliferation. At DL4, all evaluable patients showed signs of T cell expansion after 2 weeks of MT103 infusion, which was most pronounced in those who developed a partial or complete remission. The increase of CD8 T cell counts was more pronounced than that of CD4 T cells. T cell expansion was accompanied by upregulation of T cell activation markers as well as by increases in serum concentrations of cytokines like IFN-γ. T cell expansion and activation reverted in all cases when the infusion of MT103 was stopped. In summary, MT103 induced a reversible secondary T cell response involving T cell activation and proliferation as well as T cell cytotoxicity against circulating B cells and lymphoma tissue. The dose-dependent T cell expansion observed during long-term infusion of MT103, particularly within the cytotoxic TEM subset of CD8 T cells, appears to play a key role for clinical activity.

Efficacy, safety, and immune activation with pegylated human IL-10 (AM0010) plus FOLFOX in metastatic pancreatic adenocarcinoma (PDAC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4111-4111
Author(s):  
J. Randolph Hecht ◽  
Gerald Steven Falchook ◽  
Manish R. Patel ◽  
Raid Aljumaily ◽  
Jeffrey R. Infante ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
De Novo ◽  
Response Assessment ◽  
Dose Schedule ◽  
Tissue Samples ◽  
Prior Therapy ◽  
Immune Therapies

4111 Background: Oxaliplatin or nal-irinotecan plus 5-FU are used as 2nd-line PDAC therapy (mOS 5-6 months (m)). PDAC also has been largely refractory to immune therapies which may depend on the expansion of activated, intratumoral, tumor specific cytotoxic CD8+ T cells that are low in most PDACs. AM0010 stimulates survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune activation, durable stable disease and a 1yr survival of 22.5% was seen in salvage PDAC patients (pts) receiving AM0010 alone. Platins or 5-FU may activate immune responses to cancer and AM0010 has shown synergistic anti-tumor results with FOLFOX in preclinical models. In this phase 1b clinical study, the safety and efficacy of AM0010 +FOLFOX was studied in PDAC pts. Methods: PDAC pts progressing on a median of 1 prior therapy (range 1-3) were treated with AM0010 (5ug/kg SQ, qd) + FOLFOX (n = 21), an additional 4 pts with prior oxaliplatin and 5-FU were included in the safety population (n = 25). Tumor responses were assessed using irRC. Serum cytokines, activation of blood derived T cells and peripheral T cell clonality were analyzed. Pretreatment archival tissue samples were evaluated by IHC for tumor infiltration by CD8+ T cells. Results: On AM0010 + FOLFOX, G3/4 TrAEs included thrombocytopenia (52%), anemia (36%) and neutropenia (36%). A modified AM0010 dose schedule (5 days on 2 days off) avoided G3/4 thrombocytopenia. As of 01/31/2017, 2 patients remained on treatment for > 1 year. 19 pts had objective tumor response assessment; 2 had irCR, 1 irPR, 11 irSD. ORR is 15.8%, DCR is 73.7%. With median follow-up of 11.0 m (range 5.8-16.3), mPFS was 3.5 m and mOS 10.0 m. Pts with more intra-tumoral CD8+ T cells had longer OS. AM0010 + FOLFOX increased serum Th1 cytokines and reduced mediators of chronic inflammation and TGFb. AM0010 induced de-novo oligoclonal expansion of T cell clones in patients with prolonged survival. Conclusions: AM0010 plus FOLFOX is well tolerated in patients with PDAC. The observed immune activation including clonal T cell expansion and prolonged objective tumor responses are encouraging in this advanced PDAC population. This regimen is currently being studied in a phase 3 trial. Clinical trial information: NCT02009449.

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