Transient TCR-based T cell therapy in a patient with advanced treatment-resistant MSI-high colorectal cancer.

We previously demonstrated the antitumor effectiveness of transiently T cell receptor (TCR)-redirected T cells recognizing a frameshift mutation in transforming growth factor beta receptor 2. We here describe a clinical protocol using mRNA TCR-modified T cells to treat a patient with progressive, treatment-resistant metastatic microsatellite instability-high (MSI-H) colorectal cancer. Following 12 escalating doses of autologous T cells electroporated with in-vitro-transcribed Radium-1 TCR mRNA, we assessed T cell cytotoxicity, phenotype, and cytokine production.

ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma.

Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as promising as in some other cancer types due to intra-tumor heterogeneity and considerable off-target expression of the potentially targetable proteins. Here we show that chimeric antigen receptor (CAR) T cells could successfully target an isoform of alkaline phosphatase, ALPL-1, which is highly and specifically expressed in primary and metastatic OS.

Durable and dynamic hTERT immune responses following vaccination with the long-peptide cancer vaccine UV1: long-term follow-up of three phase I clinical trials.

Background: Therapeutic cancer vaccines represent a promising approach to improve clinical outcomes with immune checkpoint inhibition. UV1 is a second generation telomerase-targeting therapeutic cancer vaccine being investigated across multiple indications. Although telomerase is a near-universal tumor target, different treatment combinations applied across indications may affect the induced immune response.

Emerging Biomarkers for Immunotherapy in Glioblastoma.

Immunotherapy has shown clinical benefits in several solid malignancies-in particular, melanoma and non-small cell lung cancer. However, in other solid tumours such as glioblastoma (GBM), the response to immunotherapy has been more variable, and except for anti-PD-1 for patients with microsatellite instable (MSI)+ cancers, no immunotherapy is currently approved for GBM patients. GBM is the most common and most aggressive brain cancer with a very poor prognosis and a median overall survival of 15 months.

Peptide vaccine targeting mutated : a potential novel treatment for pseudomyxoma peritonei.

Background: Pseudomyxoma peritonei (PMP) is a rare, slow-growing abdominal cancer with no efficacious treatment options in non-resectable and recurrent cases. Otherwise, rare activating mutations in the oncogene are remarkably frequent in PMP and the mutated gene product, guanine nucleotide-binding protein α subunit (Gsα), is a potential tumor neoantigen, presenting an opportunity for targeting by a therapeutic cancer vaccine.

Methods: Tumor and blood samples were collected from 25 patients undergoing surgery for PMP (NCT02073500).

Rab7b regulates dendritic cell migration by linking lysosomes to the actomyosin cytoskeleton.

Lysosomal signaling facilitates the migration of immune cells by releasing Ca2+ to activate the actin-based motor myosin II at the cell rear. However, how the actomyosin cytoskeleton physically associates to lysosomes is unknown. We have previously identified myosin II as a direct interactor of Rab7b, a small GTPase that mediates the transport from late endosomes/lysosomes to the trans-Golgi network (TGN).

"Built-in" PD-1 blocker to rescue NK-92 activity from PD-L1-mediated tumor escape mechanisms.

Success of adoptive cell therapy mainly depends on the ability of immune cells to persist and function optimally in the immunosuppressive tumor microenvironment. Although present at the cancer site, immune cells become exhausted and/or inhibited, due to the presence of inhibitory receptors such as PD-L1 on malignant cells. Novel genetic strategies to manipulate the PD1/PD-L1 axis comprise (i) PD-1 reversion where the receptor intracellular domain is replaced with an activating unit, (ii) the use of anti-PD-L1 CAR or (iii) the disruption of the PD-1 gene.

Posttransplantation Lymphoproliferative Disease Treated by Retransplantation.

Epstein-Barr virus- (EBV-) induced posttransplantation lymphoproliferative disease (PTLD) is a life-threatening complication following allogeneic stem cell transplantation. The main risk factor is anti-thymocyte globulin (ATG). Patients who fail first-line treatment with rituximab have a poor prognosis.

Correction to: Preclinical assessment of transiently TCR redirected T cells for solid tumour immunotherapy.

The original version of this article unfortunately included a mistake in Fig. 2b where the images of mice in the tumour control group (right), day 30 (bottom) should be removed as the wrong images (duplicate of day 17) were inserted by mistake. At this time point the tumour control mice were no longer alive and the images were replaced by black areas.

Preclinical assessment of transiently TCR redirected T cells for solid tumour immunotherapy.

Off-target toxicity due to the expression of target antigens in normal tissue or TCR cross-reactivity represents a major risk when using T cell receptor (TCR)-engineered T cells for treatment of solid tumours. Due to the inherent cross-reactivity of TCRs it is difficult to accurately predict their target recognition pre-clinically. It has become evident that direct testing in a human being represents the best evaluation of the risks.

Antigen-delivery through invariant chain (CD74) boosts CD8 and CD4 T cell immunity.

Eradication of tumors by the immune system relies on the efficient activation of a T-cell response. For many years, the main focus of cancer immunotherapy has been on cytotoxic CD8 T-cell. However, stimulation of CD4 helper T cells is critical for the promotion and maintenance of immune memory, thus a good vaccine should evoke a two-dimensional T-cell response.

NK cells specifically TCR-dressed to kill cancer cells.

Background: Adoptive T-cell transfer of therapeutic TCR holds great promise to specifically kill cancer cells, but relies on modifying the patient's own T cells ex vivo before injection. The manufacturing of T cells in a tailor-made setting is a long and expensive process which could be resolved by the use of universal cells. Currently, only the Natural Killer (NK) cell line NK-92 is FDA approved for universal use.

Human c-SRC kinase (CSK) overexpression makes T cells dummy.

Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide-MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use.

Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA.

T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However, CARs recognize all CD19 positive (pos) cells, and durable responses are linked to profound depletion of normal B cells. Here, we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs), in contrast to CARs, are restricted by HLA.

Unpredicted phenotypes of two mutants of the TcR DMF5.

When a T-cell Receptor (TcR) interacts with its cognate peptide-MHC (pMHC), it triggers activation of a signaling cascade that results in the elicitation of a T cell effector function. Different models have been proposed to understand which parameters are needed to obtain an optimal activation of the signaling. It was speculated that improving the binding of a TcR could bring a stronger pMHC recognition, hence a stronger stimulation of the T cell.

T cells raised against allogeneic HLA-A2/CD20 kill primary follicular lymphoma and acute lymphoblastic leukemia cells.

T cells mediating a graft-versus-leukemia/lymphoma effects without causing graft-versus-host disease would greatly improve the safety and applicability of hematopoietic stem cell transplantation. We recently demonstrated that highly peptide- and HLA-specific T cells can readily be generated against allogeneic HLA-A*02:01 in complex with a peptide from the B cell-restricted protein CD20. Here, we show that such CD20-specific T cells can easily be induced from naïve precursors in cord blood, demonstrating that they do not represent cross-reactive memory cells.

Induction of plasma (TRAIL), TNFR-2, Fas ligand, and plasma microparticles after human immunodeficiency virus type 1 (HIV-1) transmission: implications for HIV-1 vaccine design.

The death of CD4(+) CCR5(+) T cells is a hallmark of human immunodeficiency virus (HIV) infection. We studied the plasma levels of cell death mediators and products--tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), Fas ligand, TNF receptor type 2 (TNFR-2), and plasma microparticles--during the earliest stages of infection following HIV type 1 (HIV-1) transmission in plasma samples from U.S.