In the first-ever (sanctioned) investigational use of multiple edits to the human genome, a study found that cells edited in three specific ways and then removed from patients and brought back into the lab setting were able to kill cancer months after their original manufacturing and infusion.

This is the first U.S. clinical trial to test the gene editing approach in humans, and the publication of this new data today follows on the initial report last year that researchers were able to use CRISPR/Cas9 technology to successfully edit three cancer patients' immune cells. The ongoing study is a cooperative between Tmunity Therapeutics, the Parker Institute for Cancer Immunotherapy, and the University of Pennsylvania. 

Patients on this trial were treated by Edward A. Stadtmauer, MD, section chief of Hematologic Malignancies at Penn, co-lead author on the study. The approach in this study is closely related to CAR T cell therapy, in which patient immune cells are engineered to fight cancer, but it has some key differences. Just like CAR T, researchers in this study began by collecting a patient's T cells from blood. However, instead of arming these cells with a receptor against a protein such as CD19, the team first used CRISPR/Cas9 editing to remove three genes. The first two edits removed a T cell's natural receptors so they can be reprogrammed to express a synthetic T cell receptor, allowing these cells to seek out and destroy tumors. The third edit removed PD-1, a natural checkpoint that sometimes blocks T cells from doing their job. 

Once the three genes are knocked out, a fourth genetic modification was accomplished using a lentivirus to insert the cancer-specific synthetic T cell receptor, which tells the edited T cells to target an antigen called NY-ESO-1. Previously published data show these cells typically survive for less than a week, but this new analysis shows the edited cells used in this study persisted, with the longest follow up at nine months. 

Several months after the infusion, researchers drew more blood and isolated the CRISPR-edited cells for study. When brought back into the lab setting, the cells were still able to kill tumors. 

The CRISPR-edited T cells used in this study are not active on their own like CAR T cells. Instead, they require the cooperation of a molecule known as HLA-A*02:01, which is only expressed in a subset of patients. This means that patients had to be screened ahead of time to make sure they were a match for the approach. Participants who met the requirements received other clinically-indicated therapy as needed while they waited for their cells to be manufactured. Once that process was completed, all three patients received the gene-edited cells in a single infusion after a short course of chemotherapy. Analysis of blood samples revealed that all three participants had the CRISPR-edited T cells take root and thrive in the patients. While none responded to the therapy, there were no treatment-related serious adverse events. 

CRISPR technology has not previously been tested in humans in the U.S. so the research team had to move through a comprehensive and rigorous series of institutional and federal regulatory approval steps, including approval by the National Institutes of Health's Recombinant DNA Research Advisory Committee and review by the U.S. Food and Drug Administration, as well as Penn's institutional review board and institutional biosafety committee. The entire process required more than two years.

 Researchers say these new data will open the door to later stage studies to investigate and extend this approach to a broader field beyond cancer, several of which are already planned at Penn.

After a newborn (born to a mother infected with the 2019 novel coronavirus disease (COVID-19) testing positive for COVID-19 infection within 36 hours of birth, there were concerns about whether the virus could be contracted in the womb. A new study finds that COVID-19 does not pass to the child while in the womb. The women in the small study were from Wuhan, China, in the third trimester of pregnancy and had pneumonia caused by COVID-19. However, it only included women who were late in their pregnancy and gave birth by caesarean section. 

There were two cases of fetal distress but all nine pregnancies resulted in live births. That symptoms from COVID-19 infection in pregnant women were similar to those reported in non-pregnant adults, and no women in the study developed severe pneumonia or died.

All mothers in the study were aged between 26-40 years. None of them had underlying health conditions, but one developed gestational hypertension from week 27 of her pregnancy, and another developed pre-eclampsia at week 31. Both patients’ conditions were stable during pregnancy. The nine women in the study had typical symptoms of COVID-19 infection, and were given oxygen support and antibiotics. Six of the women were also given antiviral therapy. In the study, the medical records of nine pregnant women who had pneumonia caused by COVID-19 infection were retrospectively reviewed. Infection was lab-confirmed for all women in the study, and the authors studied the nine women’s symptoms.

In addition, samples of amniotic fluid, cord blood, neonatal throat swabs and breast milk were taken for six of the nine cases [2] and tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Importantly, the samples of amniotic fluid, cord blood, and neonatal throat swabs were collected in the operating room at the time of birth to guarantee that samples were not contaminated and best represented intrauterine conditions. All nine pregnancies resulted in live births, and there were no cases of neonatal asphyxia. Four women had pregnancy complications (two had fetal distress and two had premature rupture of membrane), and four women had preterm labor which was not related to their infection and occurred after 36 gestational weeks. Two of the prematurely born newborns had a low birth weight.

The authors note that their findings are similar to observations of the severe acute respiratory syndrome (SARS) virus in pregnant women, where there was no evidence of the virus being passed from mother to child during pregnancy or birth. The findings are based on a limited number of cases, over a short period of time, and the effects of mothers being infected with the virus during the first or second trimester of pregnancy and the subsequent outcomes for their offspring are still unclear, as well as whether the virus can be passed from mother to child during vaginal birth.

Dr Jie Qiao (who was not involved in the study) of Peking University Third Hospital, China,compares the effects of the virus to those of SARS, and says: “Previous studies have shown that SARS during pregnancy is associated with a high incidence of adverse maternal and neonatal complications, such as spontaneous miscarriage, preterm delivery, intrauterine growth restriction, application of endotracheal intubation, admission to the intensive care unit, renal failure, and disseminated intravascular coagulopathy. However, pregnant women with COVID-19 infection in the present study had fewer adverse maternal and neonatal complications and outcomes than would be anticipated for those with SARS-CoV-1 infection. Although a small number of cases was analysed and the findings should be interpreted with caution, the findings are mostly consistent with the clinical analysis done by Zhu and colleagues of ten neonates born to mothers with COVID-19 pneumonia."