Search Results (7)

Target modules (TMs), intermediate molecules required for UniCAR T-cell therapy, are promising molecules for immunotheranostic approaches. In the current work, we developed TMs containing a monomeric or dimeric form of the antagonist bombesin peptide (BBN2) and assessed their potential for diagnostic imaging using positron emission tomography (PET) as well as immunotherapy in combination with UniCAR T-cells to target and image GRPR expression in prostate cancer. Synthesized monomeric and dimeric BBN2 TMs retained binding to GRPR in vitro. Both BBN2 TMs specifically activated and redirected UniCAR T-cells to eradicate PC3 and LNCaP cancer cells with high efficiency and in a comparable manner. UniCAR T-cells retained a non-exhausted memory phenotype favorable to their persistence and fitness. The ⁶⁸Ga-labeled BBN2 TMs showed proof-of-target towards GRPR in PC3 and LNCaP xenografts with similar uptake profiles for both BBN2 TMs in dynamic PET experiments. Clearance occurred exclusively through renal elimination. A tremendously increased in vivo metabolic stability of the BBN2 TMs was observed compared to their counterparts without E5B9. Both monomeric and dimeric BBN2 TMs represent novel and promising immunotheranostic tools for application in prostate cancer with exceptionally high in vivo metabolic stability. Full article

Allogeneic stem cell transplant (ASCT) remains the only treatment option for patients with high-risk acute myeloid leukemia (AML). Recurrence of leukemic cells after ASCT represents a dramatic event associated with a dismal outcome, with a 2-year survival rate of around 20%. Adoptive cell therapy (ACT) is a form of cell-based strategy that has emerged as an effective therapy to treat and prevent post-ASCT recurrence. Lymphocytes are the principal cells used in this therapy and can be derived from a hematopoietic stem cell donor, the patient themselves, or healthy donors, after being engineered to express the chimeric antigen receptor (CAR-T and UniCAR-T). In this review, we discuss recent advances in the established strategy of donor lymphocyte infusion (DLI) and the progress and challenges of CAR-T cells. Full article

Although Chimeric Antigen Receptor (CAR) T-cells have shown high efficacy in hematologic malignancies, they can cause severe to life-threatening side effects. To address these safety concerns, we have developed adaptor CAR platforms, like the UniCAR system. The redirection of UniCAR T-cells to target cells relies on a Target Module (TM), containing the E5B9 epitope and a tumor-specific binding moiety. Appropriate UniCAR-T activation thus involves two interactions: between the TM and the CAR T-cell, and the TM and the target cell. Here, we investigate if and how alterations of the amino acid sequence of the E5B9 UniCAR epitope impact the interaction between TMs and the UniCAR. We identify the new epitope E5B9L, for which the monoclonal antibody 5B9 has the greatest affinity. We then integrate the E5B9L peptide in previously established TMs directed to Fibroblast Activation Protein (FAP) and assess if such changes in the UniCAR epitope of the TMs affect UniCAR T-cell potency. Binding properties of the newly generated anti-FAP-E5B9L TMs to UniCAR and their ability to redirect UniCAR T-cells were compared side-by-side with the ones of anti-FAP-E5B9 TMs. Despite a substantial variation in the affinity of the different TMs to the UniCAR, no significant differences were observed in the cytotoxic and cytokine-release profiles of the redirected T-cells. Overall, our work indicates that increasing affinity of the UniCAR to the TM does not play a crucial role in such adaptor CAR system, as it does not significantly impact the potency of the UniCAR T-cells. Full article

Chimeric antigen receptor (CAR)-expressing T-cells are without a doubt a breakthrough therapy for hematological malignancies. Despite their success, clinical experience has revealed several challenges, which include relapse after targeting single antigens such as CD19 in the case of B-cell acute lymphoblastic leukemia (B-ALL), and the occurrence of side effects that could be severe in some cases. Therefore, it became clear that improved safety approaches, and targeting multiple antigens, should be considered to further improve CAR T-cell therapy for B-ALL. In this paper, we address both issues by investigating the use of CD10 as a therapeutic target for B-ALL with our switchable UniCAR system. The UniCAR platform is a modular platform that depends on the presence of two elements to function. These include UniCAR T-cells and the target modules (TMs), which cross-link the T-cells to their respective targets on tumor cells. The TMs function as keys that control the switchability of UniCAR T-cells. Here, we demonstrate that UniCAR T-cells, armed with anti-CD10 TM, can efficiently kill B-ALL cell lines, as well as patient-derived B-ALL blasts, thereby highlighting the exciting possibility for using CD10 as an emerging therapeutic target for B-cell malignancies. Full article

Due to its overexpression on the surface of prostate cancer (PCa) cells, the prostate stem cell antigen (PSCA) is a potential target for PCa diagnosis and therapy. Here we describe the development and functional characterization of a novel IgG4-based anti-PSCA antibody (Ab) derivative (anti-PSCA IgG4-TM) that is conjugated with the chelator DOTAGA. The anti-PSCA IgG4-TM represents a multimodal immunotheranostic compound that can be used (i) as a target module (TM) for UniCAR T cell-based immunotherapy, (ii) for diagnostic positron emission tomography (PET) imaging, and (iii) targeted alpha therapy. Cross-linkage of UniCAR T cells and PSCA-positive tumor cells via the anti-PSCA IgG4-TM results in efficient tumor cell lysis both in vitro and in vivo. After radiolabeling with ⁶⁴Cu²⁺, the anti-PSCA IgG4-TM was successfully applied for high contrast PET imaging. In a PCa mouse model, it showed specific accumulation in PSCA-expressing tumors, while no uptake in other organs was observed. Additionally, the DOTAGA-conjugated anti-PSCA IgG4-TM was radiolabeled with ²²⁵Ac³⁺ and applied for targeted alpha therapy. A single injection of the ²²⁵Ac-labeled anti-PSCA IgG4-TM was able to significantly control tumor growth in experimental mice. Overall, the novel anti-PSCA IgG4-TM represents an attractive first member of a novel group of radio-/immunotheranostics that allows diagnostic imaging, endoradiotherapy, and CAR T cell immunotherapy. Full article

Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in HNSCC patients treated with primary radiochemotherapy or postoperative radiochemotherapy, suggesting that CD98hc could be a target for HNSCC radiosensitization. One of the targeted strategies for tumor radiosensitization is precision immunotherapy, e.g., the use of chimeric antigen receptor (CAR) T cells. This study aimed to define the potential clinical value of new treatment approaches combining conventional radiotherapy with CD98hc-targeted immunotherapy. To address this question, we analyzed the antitumor activity of the combination of fractionated irradiation and switchable universal CAR (UniCAR) system against radioresistant HNSCC cells in 3D culture. CD98hc-redirected UniCAR T cells showed the ability to destroy radioresistant HNSCC spheroids. Also, the infiltration rate of the UniCAR T cells was enhanced in the presence of the CD98hc target module. Furthermore, sequential treatment with fractionated irradiation followed by CD98hc-redirected UniCAR T treatment showed a synergistic effect. Taken together, our obtained data underline the improved antitumor effect of the combination of radiotherapy with CD98hc-targeted immunotherapy. Such a combination presents an attractive approach for the treatment of high-risk HNSCC patients. Full article

Although showing impressive therapeutic potential, treatments of leukemias with T-cells expressing chimeric antigen receptors (CARs) is limited by their risk of several severe side effects. To overcome these problems, a switchable CAR platform has been developed termed UniCAR. Unlike conventional CAR, which is directed against tumor-associated antigens, UniCAR treatment involves an intermediate target module (TM), which can cross-link UniCAR T cells with tumor cells and lead to destruction. The development of these novel TMs against different tumor targets requires numerous repetitive tests on different synthesizing trials, which is usually limited in quantity and time-consuming. Meanwhile, nano-biosensors are lately known as analytical tools, which are highly sensitive, label-free, rapid and reagent-saving. Among them, silicon nanowire (SiNW) sensors have been extensively investigated by researchers over the past decades thanks to their compatibility with CMOS technology, enabling mass production. In this work, we demonstrated the application of a previously published SiNW biosensor on the detection of the binding of UniCAR and a part of different TMs. The results underline the advantages of the SiNW sensor over the ELISA method in terms of ease of preparation, speed and sensitivity. The method is able to evaluate the binding affinity of UniCAR to different TMs and open a potential to quantify the number of active UniCAR T-cells in an in vivo sample at a later stage. In the end, the application of a nanosensor may speed up the R&D process of the UniCAR concept and later play an important role in clinical monitoring of immunotherapy, especially in the era of precision medicine. Full article