First-in-Human Dose Escalation Trial To Evaluate the Clinical Safety and Efficacy of an Anti-MAGEA1 Autologous Tcr-Transgenic T Cell Therapy in Relapsed and Refractory Solid Tumors

RATIONALE OF THE TRIAL: Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors. TRIAL DESIGN: The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of 16 patients. IMA202 consists of autologous genetically modified cytotoxic CD8 CONCLUSION: In conclusion, IMA202 had a manageable safety profile, and it was associated with biological and potential clinical activity of MAGEA1-targeting genetically engineered TCR-T cells in a poor prognosis, multi-indication solid tumor cohort

Investigation of the role of target cell factors in retrovirus transduction

Gene therapy is the intracellular delivery of genetic material for a therapeutic effect and is currently being used in clinical trials for the treatment of cancer, AIDS and vascular diseases. Recombinant retroviral vectors are one of the most commonly used gene delivery vectors in clinical trials because they can permanently integrate the therapeutic gene into the genome of the target cell resulting in persistent gene expression. However, recombinant retroviral vectors suffer from several limitations. The gene transfer efficiency is not high enough to produce a desired therapeutic effect and the vectors lack the ability to genetically modify target tissue without producing unpredictable side- effects on healthy bystander tissue. The focus of this thesis is to determine target cell factors that affect efficiency and specificity of gene transfer of recombinant retroviruses. Successful gene transfer by recombinant retroviruses is a multi-step process and we have focused our efforts on those target cell factors that affect virus entry into the target cell. We have developed an experimental system to study the effect of pathway of virus entry and the intracellular trafficking itinerary of the targeted receptor, on the efficiency of gene transfer of targeted retroviruses. Our results indicate that interaction with a targeted receptor affects the efficiency of gene transfer of a targeted retrovirus by altering the residence time of the virus on the cell surface, by changing the region of the cell surface that the virus is exposed to, with respect to its natural receptor or by changing the pH that the virus is exposed to during intracellular transport. We have examined if recombinant retroviruses are capable of inducing signaling events in target cells to overcome barriers to efficient gene transfer. We have found that retroviruses are capable of activating actin-regulating-GTPase Rac1 while entering target cells. We have found that retroviruses use non-envelope and non-receptor molecules to induce Rac1 activation. Rac1 activity is important for efficient fusion and intracellular trafficking of the virus and blocking mediators of Rac1 activity on target cells affects the efficiency of gene transfer of recombinant retroviruses. The implications of our findings on efficient retrovirus-cell interactions are discussed.Ph.D.Committee Chair: Joseph Le Doux; Committee Co-Chair: Mark Prausnitz; Committee Member: Athanassios Sambanis; Committee Member: Harish Radhakrishna; Committee Member: Richard Compans; Committee Member: Timothy Wic

First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors

Rationale of the trial Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors.Trial design The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of 16 patients. IMA202 consists of autologous genetically modified cytotoxic CD8+ T cells expressing a T cell receptor (TCR), which is specific for a nine amino acid peptide derived from MAGEA1. Eligible patients underwent leukapheresis, T cells were isolated, transduced with lentiviral vector carrying MAGEA1-specific TCR and following lymphodepletion (fludarabine/cyclophosphamide), infused with a median of 1.4×109 specific T cells (range, 0.086×109–2.57×109) followed by interleukin 2.Safety of IMA202 No DLT was observed. The most common grade 3–4 adverse events were cytopenias, that is, neutropenia (81.3%), lymphopenia (75.0%), anemia (50.0%), thrombocytopenia (50.0%) and leukopenia (25.0%). 13 patients experienced cytokine release syndrome, including one grade 3 event. Immune effector cell-associated neurotoxicity syndrome was observed in two patients and was grade 1 in both.Efficacy of IMA202 Of the 16 patients dosed, 11 (68.8%) patients had stable disease (SD) as their best overall response (Response Evaluation Criteria in Solid Tumors V.1.1). Five patients had initial tumor shrinkage in target lesions and one patient with SD experienced continued shrinkage in target lesions for 3 months in total but had to be classified as progressive disease due to progressive non-target lesions. IMA202 T cells were persistent in peripheral blood for several weeks to months and were also detectable in tumor tissue. Peak persistence was higher in patients who received higher doses.Conclusion In conclusion, IMA202 had a manageable safety profile, and it was associated with biological and potential clinical activity of MAGEA1-targeting genetically engineered TCR-T cells in a poor prognosis, multi-indication solid tumor cohort.Trial registration numbers NCT04639245, NCT05430555

A review on advances in graphene-derivative/polysaccharide bionanocomposites: Therapeutics, pharmacogenomics and toxicity

Graphene-based bionanocomposites are employed in several ailments, such as cancers and infectious diseases, due to their large surface area (to carry drugs), photothermal properties, and ease of their functionalization (owing to their active groups). Modification of graphene-derivatives with polysaccharides is a promising strategy to decrease their toxicity and improve target ability, which consequently enhances their biotherapeutic efficacy. Herein, functionalization of graphene-based materials with carbohydrate polymers (e.g., chitosan, starch, alginate, hyaluronic acid, and cellulose) are presented. Subsequently, recent advances in graphene nanomaterial/polysaccharide-based bionanocomposites in infection treatment and cancer therapy are comprehensively discussed. Pharmacogenomic and toxicity assessments for these bionanocomposites are also highlighted to provide insight for future optimized and smart investigations and researches. © 2020 Elsevier Lt