A Phase 1/2 interventional study of PD-1 and ACE2 Knockout T Cells and PD-1 and ACE2 Knockout T Cells in COVID-19 Respiratory Infection, sponsored by Mahmoud Ramadan mohamed Elkazzaz. Status unknown. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2021-08-16.
Sponsored by Mahmoud Ramadan mohamed Elkazzaz · Phase 1/2, Interventional, and Treatment
T-cell exhaustion may limit long-term immunity in COVID-19 patients. T cells can lose their ability to fight viruses and tumors when they have prolonged exposure to these enemies. New data suggests people who experience mild COVID-19 symptoms show the molecular signs of exhausted memory T cells and therefore could have a reduced ability to fight reinfection. On contrary people who develop severe COVID-19 symptoms may be better protected from reinfection. A recent study reported that the 82.1% of COVID-19 cases displayed low circulating lymphocyte counts . It has been reported that, in the case of chronic viruses, continuous PD-1 expression causes T-cell exhaustion, and impairs the ability of killing the infectious cells . The adumbration of patients with COVID-19 is characterized by a diminished lymphocyte percentage, with a similar proportion of CD4+ and CD8+ T-cells. The quantity of T-cells, mostly CD8+ T-cells, presenting high expression rates of late activity marker CD25 and exhaustion marker PD-1 increases. Therefore, SARS-CoV-2 is able to make changes by modifying the acquired immune system, including B and T cells. According to experiments, PD-1's expression, as an important factor in the induction and maintenance of circumferential tolerance keeping the stability of T-cells, has been found to have a higher percentage in different cells of COVID-19 patients. In an experiment conducted by Diao et al., on the patients with SARS-CoV-2, it was observed that the expression of PD-1 on the surface of T-cells was increased significantly; it was also shown that during the SARS-CoV-2 -induced disease, additional expressions of PD-1 and Tim-3 on the T-cells were directly related to the disease's severity; the factors that were also increased in other viral infections. T cell exhaustion" phenomenon could be reversed relatively easily, for example when the T cells are no longer exposed to the virus or tumor. But unfortunately, although exhausted T cells recovered from chronic infection (REC-TEX) regain some function and features of memory T cells (TMEM), they retain epigenetic scars indicating the control of gene expression is "locked in" to their exhaustion history. Once T cells become exhausted, they remain fundamentally 'wired' to be exhausted-thus it may be hard to get them to become effective virus- and cancer-fighters again," said John Wherry, PhD, chair of the department of Systems Pharmacology and Translational Therapeutics and director of the Penn Institute of Immunology in the Perelman School of Medicine at the University of Pennsylvania. Furthermore, COVID-19 may infect T lymphocyte cells and induce apoptosis and apoptotic markers. Lymphocytopenia was also found in the Middle East respiratory syndrome (MERS) cases. MERS-CoV can directly infect human primary T lymphocytes and induce T-cell apoptosis through extrinsic and intrinsic apoptosis pathways, but it cannot replicate in T lymphocytes. However, it is unclear whether SARS-CoV-2 can also infect T cells, resulting in lymphocytopenia. A study showed that T cells express a very low expression level of hACE2 on its cell surface and T-cell lines were significantly more sensitive to SARS-CoV-2 infection when compared with SARS-CoV . In other words, these results tell us that T lymphocytes may be more permissive to SARS-CoV-2 infection. Therefore, it is plausible that the S protein of SARS-CoV-2 might mediate potent infectivity, even on cells expressing low hACE2, which would, in turn, explain why the transmission rate of SARS-CoV-2 is so high. Through recent advances in genomic editing, T cells can now be successfully modified via CRISPR/Cas9 technology. For instance, engaging (post-)transcriptional mechanisms to enhance T cell cytokine production, the retargeting of T cell antigen specificity or rendering T cells refractive to inhibitory receptor signaling can augment T cell effector function. Therefore, CRISPR/Cas9-mediated genome editing might provide novel strategies for inducing long term immunity against COVID-19.Immunotherapies with autologous T cells have become a powerful treatment option for many diseases like viral infection or cancer. These include the adoptive isolation and transfer of naturally-occurring virus/tumor-specific T cells and the transfer of T lymphocytes that have been genetically modified . According to the investigator, exhausted virus-reactive CD8+ memory T cells will be isolated from patients with mild infection using a modified antigen-reactive T cell enrichment (ARTE) assay. exhausted virus-reactive CD8+ memory T cells will be collected and both Programmed cell death protein 1(PDCD1) gene and ACE2 gene will be knocked out by CRISPR Cas9 in the laboratory. The lymphocytes will be selected and expanded ex vivo and infused back into patients.
This study will assess the safety of PD-1 and ACE2 knockout engineered T cells as genetically modified memory T cells capable of providing long-term immunity against COVID-19 by remembering and killing the virus if it is reintroduced. Blood samples will also be collected for research purposes. This is a dose-escalation study of ex-vivo knocked-out, expanded, and selected PD-1 and ACE2 knockout-T cells from autologous origin. Patients are assigned to 1 of 3 treatment groups to determine the maximal tolerant dose. After the lower number of cycles are considered tolerant, an arm of the next higher number of cycles will be open to next patients. Biomarkers and immunological markers are collected and analyzed as well. According to the investigator, exhausted virus-reactive CD8+ memory T cells will be isolated from patients with mild infection using a modified antigen-reactive T cell enrichment (ARTE) assay. exhausted virus-reactive CD8+ memory T cells will be collected and Programmed cell death protein 1(PDCD1) gene and ACE2 gene will be knocked out by CRISPR Cas9 in the laboratory (PD-1 and ACE2 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. A total of 2 x 10\^7/kg PD-1 and ACE2 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Patients will receive a total of two cycles of treatment.
7,640 studies on the registry are indexed under COVID-19; 488 are open to participants now.
This study's planned enrollment of 16 is below the median of 100 across 4,099 interventional studies indexed under COVID-19.
Browse COVID-19 studies →Mahmoud Ramadan mohamed Elkazzaz is the lead sponsor of 2 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria
Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) and ACE2 gene will be knocked out by CRISPR Cas9 in the laboratory (PD-1/ACE2 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. A total of 1 x 10\^7/kg PD-1and ACE2 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Patients will receive a total of two cycles of treatment.
Drug: PD-1 and ACE2 Knockout T Cells
Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) and ACE2 gene will be knocked out by CRISPR Cas9 in the laboratory (PD-1/ACE2 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. A total of 1 x 10\^7/kg PD-1 and ACE2 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Patients will receive a total of two cycles of treatment. A total of 2 x 10\^7/kg PD-1and ACE2 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Patients will receive a total of two cycles of treatment.
Drug: PD-1 and ACE2 Knockout T Cells
Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) and ACE2 gene will be knocked out by CRISPR Cas9 in the laboratory (PD-1/ACE2 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. A total of 4 x 10\^7/kg PD-1 and ACE2 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Patients will receive a total of two cycles of treatment.
Drug: PD-1 and ACE2 Knockout T Cells
Autologous lymphocytes are collected and both PDCD1 and ACE2 gene knocked out in the laboratory. Cells are selected and expanded ex vivo. Cells are infused back to the patients for treatment
Autologous lymphocytes are collected and both PDCD1 and ACE2 gene knocked out in the laboratory. Cells are selected and expanded ex vivo. Cells are infused back to the patients for treatment
Autologous lymphocytes are collected and both PDCD1 and ACE2 gene knocked out in the laboratory. Cells are selected and expanded ex vivo. Cells are infused back to the patients for treatment
Number of Participants With Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and Tolerability of Dose of PD-1 Knockout T Cells Using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in Patients
Time frame: Dose Escalation - Approximately 5 months
Number of Patients With Overall Response to the reinfection
Time frame: 10 months
All cause mortality rate
The time from the date of first edited T cell infusion to the date of reinfection with COVID-19 or death due to any reason.
Time frame: Measured from Day 0 through Day 180
Proportion of patients with upregulated inflammatory factors
Upregulated inflammatory factors will be measured at different timepoint
Time frame: 1 month and 3 month
Serum levels of IL-6,TNF,TLR3,CRP, ESR and Type I interferon
Serum levels of IL-6,TNF,TLR3,CRP, ESR and Type I interferon will be measured at different timepoint
Time frame: 1 month and 3 month
Absolute lymphocyte counts (CD4,CD8 and CD25+FOXP3+ Regulatory T)
Absolute lymphocyte counts (CD4,CD8 and CD25+FOXP3+ Regulatory T) will be measured at different timepoint
Time frame: 1 month and 3 month
Safety-Hematology
white blood cells (WBC) Differential cell counts should be performed at baseline, at each visit during PD-1 Knockout Engineered T Cells infusion phase and thereafter at investigators discretion. Clinical status and laboratory parameters are to be followed using individual institutional guidelines and the best clinical judgment of the responsible physician, which can involve more frequent testing.
Time frame: Measured from Day 0 through Day 180
No study locations are listed for this record.
This study is status unknown, as verified in Aug 2021. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Mahmoud Ramadan mohamed Elkazzaz