Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer.

Sotigalimab is an agonistic anti-CD40 mAb that can modulate antitumor immune responses. In a phase II clinical trial of sotigalimab combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction (E/GEJ) cancer with the primary outcome of efficacy as measured by pathologic complete response (pCR) rate, the combination induced pCR in 38% of treated patients. We investigated the mechanism of action of sotigalimab in samples obtained from this clinical trial.

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma: A Phase 1 Nonrandomized Controlled Trial.

Importance: Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts.

Objective: To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions.

A Phase II Trial of the CD40 Agonistic Antibody Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Confirmed Disease Progression on Anti-PD-1 Therapy.

Purpose: Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with a unique epitope specificity and Fc receptor binding profile optimized for activation of CD40-expressing antigen-presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1.

Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma.

Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473).

First-in-Class, First-in-Human Study Evaluating LV305, a Dendritic-Cell Tropic Lentiviral Vector, in Sarcoma and Other Solid Tumors Expressing NY-ESO-1.

Purpose: LV305 is a modified, third-generation, nonreplicating, integration-deficient lentivirus-based vector designed to selectively transduce dendritic cells . LV305 induces expression of the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer testis antigen in dendritic cells, promoting immune responses against NY-ESO-1-expressing tumors. This phase I study evaluated the safety, immunogenicity, and preliminary efficacy of LV305 in patients with sarcoma or other solid tumors.

Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma.

Purpose: G100 is a toll-like receptor 4 (TLR4) agonist that triggers innate and adaptive antitumor immune responses in preclinical models. This pilot study assessed the safety, efficacy, and immunologic activity of intratumoral (IT) administration of G100 in patients with Merkel cell carcinoma (MCC).

Patients And Methods: Patients with locoregional MCC ( = 3; cohort A) received neoadjuvant IT G100 (2 weekly doses at 5 μg/dose) followed by surgery and radiotherapy; patients with metastatic MCC ( = 7; cohort B) received 3 doses in a 6-week cycle and could receive additional cycles with/without radiotherapy.

First-in-Human Treatment With a Dendritic Cell-targeting Lentiviral Vector-expressing NY-ESO-1, LV305, Induces Deep, Durable Response in Refractory Metastatic Synovial Sarcoma Patient.

Effective induction of antitumor T cells is a pivotal goal of cancer immunotherapy. To this end, lentiviral vectors (LV) are uniquely poised to directly prime CD8 T-cell responses via transduction of dendritic cells in vivo and have shown promise as active cancer therapeutics in preclinical tumor models. However, until now, significant barriers related to production and regulation have prevented their widespread use in the clinic.

Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor β by the monoclonal antibody fresolimumab (GC1008).

Fresolimumab is an antibody capable of neutralizing all human isoforms of transforming growth factor beta (TGFβ) and has demonstrated anticancer activity in investigational studies. Inhibition of TGFβ by fresolimumab can potentially result in the development of cutaneous lesions. The aim of this study was to investigate the clinical, histological, and immunohistochemical characteristics of cutaneous neoplasms associated with fresolimumab.

Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma.

Background: In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma.

TGF-β-Neutralizing Antibody 1D11 Enhances Cytarabine-Induced Apoptosis in AML Cells in the Bone Marrow Microenvironment.

Hypoxia and interactions with bone marrow (BM) stromal cells have emerged as essential components of the leukemic BM microenvironment in promoting leukemia cell survival and chemoresistance. High levels of transforming growth factor beta 1 (TGFβ1) produced by BM stromal cells in the BM niche regulate cell proliferation, survival, and apoptosis, depending on the cellular context. Exogenous TGFβ1 induced accumulation of acute myeloid leukemia (AML) cells in a quiescent G0 state, which was further facilitated by the co-culture with BM-derived mesenchymal stem cells (MSCs).

Plerixafor plus granulocyte colony-stimulating factor versus placebo plus granulocyte colony-stimulating factor for mobilization of CD34(+) hematopoietic stem cells in patients with multiple myeloma and low peripheral blood CD34(+) cell count: results of a subset analysis of a randomized trial.

Preapheresis peripheral blood (PB) CD34(+) cell count is a strong predictor of hematopoietic stem cell (HSC) mobilization and is routinely used to optimize the timing, cost, and success of HSC collection in patients with multiple myeloma. However, a uniform PB CD34(+) cell count that predicts mobilization failure has not been defined, resulting in the development of institute-specific algorithms for mobilization, particularly regarding the decision of when to use the novel stem cell mobilization agent plerixafor. In this post hoc analysis, we evaluated the mobilization efficacy of plerixafor plus granulocyte colony-stimulating factor (G-CSF) versus placebo plus G-CSF in patients with multiple myeloma, stratified by preapheresis PB CD34(+) cell count: <10, <15, <20, and ≥20 cells/μL.

The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome.

Mutations in CXCR4 cause severe leukopenia in myelokathexis or WHIM syndrome. Plerixafor inhibits binding of CXCR4 to its ligand CXCL12. We investigated the effects of plerixafor (0.

Transplanted CD34(+) cell dose is associated with long-term platelet count recovery following autologous peripheral blood stem cell transplant in patients with non-Hodgkin lymphoma or multiple myeloma.

Autologous hematopoietic stem cell transplantation (ASCT) is an established treatment for patients with hematologic malignancies, yet the impact of transplanted CD34(+) cell dose on clinical outcomes is unresolved. We conducted post hoc analyses of transplanted CD34(+) cell dose and hematopoietic recovery following ASCT in 438 patients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), using data from 2 multicenter phase 3 clinical studies that compared plerixafor plus granulocyte-colony stimulating factor (G-CSF) versus placebo plus G-CSF as stem cell mobilization regimens. Days to engraftment and the proportion of patients who reached predetermined blood count thresholds were compared across 3 CD34(+) cell dose levels: 2-4 × 10(6) cells/kg, 4-6 × 10(6) cells/kg, and >6 × 10(6) cells/kg, regardless of mobilization treatment.

Relevance and clinical implications of tumor cell mobilization in the autologous transplant setting.

Autologous transplantation of peripheral blood (PB) hematopoietic stem cells (HSCs) is a widely used strategy for reconstitution of blood cells following high-dose chemotherapy for hematologic malignancies such as multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and acute myeloid leukemia (AML), among others. Stem cells for transplantation are usually obtained from PB after treatment with chemotherapy with or without cytokine, usually granulocyte-colony stimulating factor (G-CSF), or after treatment with cytokine alone. The use of autologous peripheral blood stem cells (PBSCs) for transplantation is associated with the risk of contamination of the graft with tumor cells; whether this impacts response rates, progression-free survival (PFS), and overall survival (OS) is still debatable.

The radioisotope contributes significantly to the activity of radioimmunotherapy.

Purpose: A multicenter, randomized study was undertaken to estimate the single agent activity of Tositumomab and to determine the contribution of radioisotope-labeling with (131)I to activity and toxicity by comparing treatment outcomes for Tositumomab and Iodine I 131 Tositumomab (BEXXAR) to an equivalent total dose of unlabeled Tositumomab.

Experimental Design: Seventy-eight patients with refractory/relapsed non-Hodgkin's lymphoma were randomized to either unlabeled Tositumomab or Iodine I 131 Tositumomab. Patients progressing after unlabeled Tositumomab could cross over to receive Iodine I 131 Tositumomab.

Clinical outcome of lymphoma patients after idiotype vaccination is correlated with humoral immune response and immunoglobulin G Fc receptor genotype.

Purpose: The unique immunoglobulin idiotype (Id) expressed by each B-cell lymphoma is a target for immunotherapy. Vaccination with Id induces humoral and/or cellular anti-Id immune responses. However, the clinical impact of these anti-Id immune responses is unknown.

CTLA4 blockade maximizes antitumor T-cell activation by dendritic cells presenting idiotype protein or opsonized anti-CD20 antibody-coated lymphoma cells.

CTLA4 is a negative regulator of the costimulatory signals induced by the interaction of CD28 on T cells and B7 on dendritic cells (DCs). Antibodies (Abs) against CTLA4 can block its function and increase the activation of T cells primed to recognize antigens. The effect of CTLA4 blockade on the cross-presentation of tumor antigens by DCs to T cells was examined.

Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients.

Tumor-specific clonal immunoglobulin expressed by B-cell lymphomas (idiotype [Id]) can serve as a target for active immunotherapy. We have previously described the vaccination of 4 patients with follicular lymphoma using dendritic cells (DCs) pulsed with tumor-derived Id protein and now report on 35 patients treated using this approach. Among 10 initial patients with measurable lymphoma, 8 mounted T-cell proliferative anti-Id responses, and 4 had clinical responses--2 complete responses (CRs) (progression-free [PF] for 44 and 57 months after vaccination), 1 partial response (PR) (PF for 12 months), and 1 molecular response (PF for 75+ months).