Objective: Relapsed and refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) are the focus of studies on hematological cancers. Treatment of these malignancies has undergone recent transformation with the development of new gene therapy and molecular biology techniques, which are safer and well-tolerated therapeutic approaches. The CD19 antigen is the most studied therapeutic target in these hematological cancers. This study reports the results of clinical-grade production, quality control, and in vivo efficacy processes of ISIKOK-19 cells as the first academic clinical trial of CAR-T cells targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey. Materials and Methods: We used a lentiviral vector encoding the CD19 antigen-specific antibody head (FMC63) conjugated with the CD8-CD28-CD3 zeta; sequence as a chimeric antigen receptor (CAR) along with a truncated form of EGFR (EGFRt) on human T-lymphocytes (CAR-T). We preclinically assessed the efficacy and safety of the manufactured CAR-T cells, namely ISIKOK-19, from both healthy donors' and ALL/NHL patients' peripheral blood mononuclear cells. Results: We showed significant enhancement of CAR lentivirus transduction efficacy in T-cells using BX-795, an inhibitor of the signaling molecule TBK1/IKK epsilon, in order to cut the cost of CAR-T cell production. In addition, ISIKOK-19 cells demonstrated a significantly high level of cytotoxicity specifically against a CD19+ B-lymphocyte cancer model, RAJI cells, in NOD/SCID mice. Conclusion: This is the first report of preclinical assessment of efficacy and safety analysis of CAR-T cells (ISIKOK-19) targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey.

Purpose: This prospective clinical case series aimed to evaluate the effect of suprachoroidal implantation of mesenchymal stem cells (MSCs) in the form of spheroids as a stem cell therapy for retinitis pigmentosa (RP) patients with relatively good visual acuity. Methods: Fifteen eyes of 15 patients with RP who received suprachoroidal implantation of MSCs in the form of spheroids were included. Best-corrected visual acuity (BCVA), 10–2 and 30–2 visual field examination and multifocal electroretinography (mfERG) recordings were recorded at baseline, postoperative 1st, 3rd and 6th months during follow-up. Results: Baseline median BCVA of RP patients was 1.30 (1.00–2.00) logMAR. BCVA has improved to 1.00 (0.50–1.30), 0.80 (0.40–1.30) and 0.80 (0.40–1.30) at the postoperative 1st, 3rd and 6th months, respectively. The improvements from baseline to the 3rd and 6th months were statistically significant (p = 0.03 and p < 0.001, respectively). In the 30–2 VF test, median MD was significantly improved at the 6th month compared to baseline (p = 0.030). In the 10–2 VF test, the median MD value was significantly different at the 6th month compared to the baseline (p = 0.043). The PSD value of the 10–2 VF test was significantly different at the 6th month compared to the 3rd month (p = 0.043). The amplitudes of P1 waves in < 2°, 5°–10° and 10°–15° rings improved significantly at the postoperative 6th month (p = 0.014, p = 0.018 and p = 0.017, respectively). There was also a statistically significant improvement in implicit times of P1 waves in 10°–15° ring at the postoperative 6th month (p = 0.004). Conclusion: Suprachoroidal implantation of MSCs in the form of spheroids as a stem cell therapy for RP patients with relatively good visual acuity has an improving effect on BCVA, VF and mfERG recordings during the 6-month follow-up period. Spheroidal MSCs with enhanced effects may be more successful in preventing apoptosis and improving retinal tissue healing in RP patients.

Objective: Chimeric antigen receptor T (CAR-T) cell therapies have already made an impact on the treatment of B-cell malignancies. Although CAR-T cell therapies are promising, there are concerns about commercial products regarding their affordability and sustainability. In this preliminary study, the results of the first production and clinical data of an academic CAR-T cell (ISIKOK-19) trial in Turkey are presented. Materials and Methods: A pilot clinical trial (NCT04206943) designed to assess the safety and feasibility of ISIKOK-19 T-cell therapy for patients with relapsed and refractory CD19+ tumors was conducted and participating patients received ISIKOK-19 infusions between October 2019 and July 2021. The production data of the first 8 patients and the clinical outcome of 7 patients who received ISIKOK-19 cell infusions are presented in this study. Results: Nine patients were enrolled in the trial [5 with acute lymphoblastic leukemia (ALL) and 4 with non-Hodgkin lymphoma (NHL)], but only 7 patients could receive treatment. Two of the 3 participating ALL patients and 3 of the 4 NHL patients had complete/partial response (overall response rate: 72%). Four patients (57%) had CAR-T-related toxicities (cytokine release syndrome, CAR-T-related encephalopathy syndrome, and pancytopenia). Two patients were unresponsive and had progressive disease following CAR-T therapy. Two patients with partial response had progressive disease during follow-up. Conclusion: Production efficacy and fulfillment of the criteria of quality control were satisfactory for academic production. Response rates and toxicity profiles were also acceptable for this heavily pretreated/refractory patient group. ISIKOK-19 cells appear to be a safe, economical, and efficient treatment option for CD19+ tumors. However, the findings of this study need to be supported by the currently ongoing ISIKOK-19 clinical trial.

COVID-19 outbreak caused by SARS-CoV-2 created an unprecedented health crisis since there is no vaccine for this novel virus. Therefore, SARS-CoV-2 vaccines have become crucial for reducing morbidity and mortality. In this study, in vitro and in vivo safety and efficacy analyzes of lyophilized vaccine candidates inactivated by gamma-irradiation were performed. The candidate vaccines in this study were OZG-3861 version 1 (V1), an inactivated SARS-CoV-2 virus vaccine, and SK-01 version 1 (V1), a GM-CSF adjuvant added vaccine. The candidate vaccines were applied intradermally to BALB/c mice to assess toxicity and immunogenicity. Preliminary results in vaccinated mice are reported in this study. Especially, the vaccine models containing GM-CSF caused significant antibody production with neutralization capacity in absence of the antibody-dependent enhancement feature, when considered in terms of T and B cell responses. Another important finding was that the presence of adjuvant was more important in T cell in comparison with B cell response. Vaccinated mice showed T cell response upon restimulation with whole inactivated SARS-CoV-2 or peptide pool. This study shows that the vaccines are effective and leads us to start the challenge test to investigate the gamma-irradiated inactivated vaccine candidates for infective SARS-CoV-2 virus in humanized ACE2+ mice.

The SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A, oral polio vaccine, and smallpox proved to be reliable approaches for immunization for prolonged periods. During the pandemic, we produced an inactivated SARS-CoV-2 vaccine candidate, having the advantages of being manufactured rapidly and tested easily in comparison with recombinant vaccines. In this study, an inactivated virus vaccine that includes a gamma irradiation process for the inactivation as an alternative to classical chemical inactivation methods so that there is no extra purification required has been optimized. The vaccine candidate (OZG-38.61.3) was then applied in mice by employing the intradermal route, which decreased the requirement of a higher concentration of inactivated virus for proper immunization, unlike most of the classical inactivated vaccine treatments. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 10 ¹³ or 10 ¹⁴ viral copy per dose) of OZG-38.61.3 was initially determined in Balb/c mice. This was followed by testing the immunogenicity and protective efficacy of OZG-38.61.3. Human ACE2-encoding transgenic mice were immunized and then infected with a dose of infective SARS-CoV-2 virus for the challenge test. Findings of this study show that vaccinated mice have lower SARS-CoV-2 viral copy number in oropharyngeal specimens along with humoral and cellular immune responses against the SARS-CoV-2, including the neutralizing antibodies similar to those shown in Balb/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.

BACKGROUND The efficacy of SARS-CoV2 single donor convalescent plasma (CP) varied according to the application time and the amount of antibody that is administered. Single donor CP has some drawbacks; such as the insufficient levels of neutralizing antibody activities, the requirements of blood group compatibility, and the risk of infection transmission. In this study, the safety and efficacy of pathogen inactivated, isohemagglutinin-depleted (concentrated) and pooled CP product was investigated. METHODS A total of sixteen patients were treated with either single donor CP (n=9) or pathogen-free, concentrated, pooled CP (ACB-IP 1.0) (n=7). RESULTS Five out of six single donor plasma SARS-CoV2 antibody titers remained below 12 s/co, but the antibody titers of all ACB-IP 1.0 plasma were above 12 s/co. SARS-CoV2 total antibody titers of ACB-IP 1.0 plasma were statistically higher than the antibody titers of single donor CP. Mean total plasma neutralizing antibody activity of ACB-IP 1.0 plasma (1.5421) was found statistically higher than single donor CP (0.9642) in 1:256 dilution (ρ<0.01) The mortality rates of the patients treated with ACB-IP 1.0 plasma were statistically lower (p< 0.05) than the patients treated with single donor CP. The administration of either single donor CP or ACB-IP 1.0 plasma to the patients within eight days significantly shortened the length of hospitalization (ρ< 0.05). CONCLUSION The present study established ACB-IP 1.0 plasma product as a safe and potentially effective treatment for COVID-19, allowing rapid access to patients in need. TRIAL REGISTRATION Trial Registration Number: NCT04769245 Trial Registration Date: 17.03.2021