High-resolution profile of neoantigen-specific TCR activation links moderate stimulation to increased resilience of engineered TCR-T cells.

Neoantigen-specific T cell receptors (neoTCRs) promise safe, personalized anti-tumor immunotherapy. However, detailed assessment of neoTCR-characteristics affecting therapeutic efficacy is mostly missing. Previously, we identified diverse neoTCRs restricted to different neoantigens in a melanoma patient.

The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma.

Background: BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g.

Current and future concepts for the generation and application of genetically engineered CAR-T and TCR-T cells.

Adoptive cell therapy (ACT) has seen a steep rise of new therapeutic approaches in its immune-oncology pipeline over the last years. This is in great part due to the recent approvals of chimeric antigen receptor (CAR)-T cell therapies and their remarkable efficacy in certain soluble tumors. A big focus of ACT lies on T cells and how to genetically modify them to target and kill tumor cells.

The influence of metastatic patterns and tumor load on therapeutic efficacy of immunotherapy in patients with metastatic melanoma as determined by quantitative PET-parameters using [ 18 F]-fluorodeoxyglucose PET/computed tomography.

The introduction of immunotherapy was a revolution in the treatment of metastatic melanoma. Nevertheless, there are only few clinical parameters to predict response to immunotherapy. The purpose of this study was to identify metastatic patterns that can predict response by using noninvasive 18 F-FDG PET/CT imaging.

Paving the Way to Solid Tumors: Challenges and Strategies for Adoptively Transferred Transgenic T Cells in the Tumor Microenvironment.

T cells are important players in the antitumor immune response. Over the past few years, the adoptive transfer of genetically modified, autologous T cells-specifically redirected toward the tumor by expressing either a T cell receptor (TCR) or a chimeric antigen receptor (CAR)-has been adopted for use in the clinic. At the moment, the therapeutic application of CD19- and, increasingly, BCMA-targeting-engineered CAR-T cells have been approved and have yielded partly impressive results in hematologic malignancies.

Adoptive Cellular Therapy for Multiple Myeloma Using CAR- and TCR-Transgenic T Cells: Response and Resistance.

Despite the substantial improvement of therapeutic approaches, multiple myeloma (MM) remains mostly incurable. However, immunotherapeutic and especially T cell-based approaches pioneered the therapeutic landscape for relapsed and refractory disease recently. Targeting B-cell maturation antigen (BCMA) on myeloma cells has been demonstrated to be highly effective not only by antibody-derived constructs but also by adoptive cellular therapies.

Promise and challenges of clinical non-invasive T-cell tracking in the era of cancer immunotherapy.

In the last decades, our understanding of the role of the immune system in cancer has significantly improved and led to the discovery of new immunotherapeutic targets and tools, which boosted the advances in cancer immunotherapy to fight a growing number of malignancies. Approved immunotherapeutic approaches are currently mainly based on immune checkpoint inhibitors, antibody-derived targeted therapies, or cell-based immunotherapies. In essence, these therapies induce or enhance the infiltration and function of tumor-reactive T cells within the tumors, ideally resulting in complete tumor eradication.

Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAF mutant melanoma: safety and tolerability results from the phase I IMMU-TARGET trial.

Background: Combination of immune checkpoint inhibitors and mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi) has been proposed to enhance the durability of anti-tumour responses induced by MAPKi. Here, we present phase I safety results from an open-label, phase I/II study of pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) triplet therapy in advanced, B-Raf proto-oncogene serine/threonine kinase (BRAF)-mutated melanoma (IMMU-TARGET, NCT02902042).

Methods: The dose finding phase I part used a 3 + 3 design, starting with the approved doses of PEM (200 mg every three weeks), ENC (450 mg once daily [QD]) and BIN (45 mg twice daily [BID]) as dose level (DL) 0.

Functional analysis of peripheral and intratumoral neoantigen-specific TCRs identified in a patient with melanoma.

Background: Neoantigens derived from somatic mutations correlate with therapeutic responses mediated by treatment with immune checkpoint inhibitors. Neoantigens are therefore highly attractive targets for the development of therapeutic approaches in personalized medicine, although many aspects of their quality and associated immune responses are not yet well understood. In a case study of metastatic malignant melanoma, we aimed to perform an in-depth characterization of neoantigens and respective T-cell responses in the context of immune checkpoint modulation.

Adoptive T Cell Therapy Is Complemented by Oncolytic Virotherapy with Fusogenic VSV-NDV in Combination Treatment of Murine Melanoma.

Cancer immunotherapies have made major advancements in recent years and are becoming the prevalent treatment options for numerous tumor entities. However, substantial response rates have only been observed in specific subsets of patients since pre-existing factors determine the susceptibility of a tumor to these therapies. The development of approaches that can actively induce an anti-tumor immune response, such as adoptive cell transfer and oncolytic virotherapy, have shown clinical success in the treatment of leukemia and melanoma, respectively.

Synthesis and Preclinical Evaluation of a Ga-Labeled Adnectin, Ga-BMS-986192, as a PET Agent for Imaging PD-L1 Expression.

Blocking the interaction of the immune checkpoint molecule programmed cell death protein-1 and its ligand, PD-L1, using specific antibodies has been a major breakthrough for immune oncology. Whole-body PD-L1 expression PET imaging may potentially allow for a better prediction of response to programmed cell death protein-1-targeted therapies. Imaging of PD-L1 expression is feasible by PET with the adnectin protein F-BMS-986192.

Targeted in-vitro-stimulation reveals highly proliferative multi-virus-specific human central memory T cells as candidates for prophylactic T cell therapy.

Adoptive T cell therapy (ACT) has become a treatment option for viral reactivations in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Animal models have shown that pathogen-specific central memory T cells (TCM) are protective even at low numbers and show long-term survival, extensive proliferation and high plasticity after adoptive transfer. Concomitantly, our own recent clinical data demonstrate that minimal doses of purified (not in-vitro- expanded) human CMV epitope-specific T cells can be sufficient to clear viremia.

The Systemic Treatment of Melanoma.

Background: The systemic treatment of metastatic melanoma has improved considerably with the introduction of new, targeted substances and immune checkpoint inhibitors. This article presents treatment options for advanced inoperable melanoma and in the setting of adjuvant treatment after complete metastasectomy.

Methods: The data for analysis were derived from a selective literature search in PubMed and a search for systematic reviews in the Cochrane Library.

Key Features Relevant to Select Antigens and TCR From the MHC-Mismatched Repertoire to Treat Cancer.

Adoptive transfer of T cells transgenic for tumor-reactive T-cell receptors (TCR) is an attractive immunotherapeutic approach. However, clinical translation is so far limited due to challenges in the identification of suitable target antigens as well as TCRs that are concurrent safe and efficient. Definition of key characteristics relevant for effective and specific tumor rejection is essential to improve current TCR-based adoptive T-cell immunotherapies.

Gene editing enables T-cell engineering to redirect antigen specificity for potent tumor rejection.

Adoptive transfer of TCR transgenic T cells holds great promise for treating various cancers. So far, mainly semi-randomly integrating vectors have been used to genetically modify T cells. These carry the risk of insertional mutagenesis, and the sole addition of an exogenous TCR potentially results in the mispairing of TCR chains with endogenous ones.

Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers.

Vesicular stomatitis virus (VSV) represents an attractive oncolytic virotherapy platform because of its potent tumor cell-killing and immune-stimulating properties; yet the clinical translation of VSV faces numerous challenges, such as inefficient systemic delivery and severe side effects such as neurotoxicity. We hypothesized that we could overcome these limitations and simultaneously enhance the therapy, by combining VSV with adoptively transferred T cell receptor (TCR) transgenic T cells as carrier cells. We show that CD8 T central memory cells (CD8 T cm) can be efficiently loaded with VSV, they support intracellular virus production, and they can efficiently transfer VSV to tumor cells without compromising their own viability or antitumor reactivity.

T-cell functionality testing is highly relevant to developing novel immuno-tracers monitoring T cells in the context of immunotherapies and revealed CD7 as an attractive target.

Cancer immunotherapy has proven high efficacy in treating diverse cancer entities by immune checkpoint modulation and adoptive T-cell transfer. However, patterns of treatment response differ substantially from conventional therapies, and reliable surrogate markers are missing for early detection of responders versus non-responders. Current imaging techniques using F-fluorodeoxyglucose-positron-emmission-tomograpy (F-FDG-PET) cannot discriminate, at early treatment times, between tumor progression and inflammation.

[Immuno-Oncology: A Brief Overview].

Pioneering work has unraveled the role of the immune system in the development and control of cancer. This knowledge has set the basis for the successful implementation of immunotherapy into the standard of care for a large number of cancer types. Based on response rates and prolongation of overall survival, immunotherapeutic approaches have been approved in a growing number of tumor diseases.

Evaluation of the new continuous mononuclear cell collection protocol versus an older version on two different apheresis machines.

Background: Cell separators are routinely used to collect CD34 blood stem cells in the context of customized stem cell transplantation procedures. The Spectra Optia (Terumo BCT) is a novel development of the precursor instrument, the Cobe Spectra (Terumo BCT).

Study Design And Methods: In this report, 146 autologous and 42 allogeneic donors undergoing apheresis on the Cobe Spectra using the mononuclear cell (MNC) program 4.