Targeting solid tumor antigens with chimeric receptors: cancer biology meets synthetic immunology.

Chimeric antigen receptor (CAR) T cell therapy is a medical breakthrough in the treatment of B cell malignancies. There is intensive focus on developing solid tumor-targeted CAR-T cell therapies. Although clinically approved CAR-T cell therapies target B cell lineage antigens, solid tumor targets include neoantigens and tumor-associated antigens (TAAs) with diverse roles in tumor biology. Multiple early-stage clinical trials now report encouraging signs of efficacy for CAR-T cell therapies that target solid tumors. We review the landscape of solid tumor target antigens from the perspective of cancer biology and gene regulation, together with emerging clinical data for CAR-T cells targeting these antigens. We then discuss emerging synthetic biology strategies and their application in the clinical development of novel cellular immunotherapies.

Genetic retargeting of E3 ligases to enhance CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapies are medical breakthroughs in cancer treatment. However, treatment failure is often caused by CAR T cell dysfunction. Additional approaches are needed to overcome inhibitory signals that limit anti-tumor potency. Here, we developed bifunctional fusion "degrader" proteins that bridge one or more target proteins and an E3 ligase complex to enforce target ubiquitination and degradation. Conditional degradation strategies were developed using inducible degrader transgene expression or small molecule-dependent E3 recruitment. We further engineered degraders to block SMAD-dependent TGFß signaling using a domain from the SARA protein to target both SMAD2 and SMAD3. SMAD degrader CAR T cells were less susceptible to suppression by TGFß and demonstrated enhanced anti-tumor potency in vivo. These results demonstrate a clinically suitable synthetic biology platform to reprogram E3 ligase target specificity for conditional, multi-specific endogenous protein degradation, with promising applications including enhancing the potency of CAR T cell therapy.

Dengue serology in Indonesian COVID-19 patients: Coinfection or serological overlap?

Dengue fever is an extremely common infection in Indonesia, with an estimated 77.96 cases / 100.000 person-years in 2016. However, in 2020 the threat of extremely contagious SARS CoV-2 or COVID-19 in Indonesia emerged, which has infected more than 100.303 persons by July 28, 2020, and expected to grow exponentially except if very strict measures were implemented. There are similar symptoms and laboratory findings with both dengue fever and COVID-19, paving way to dangerous possibilities such as incorrect or delayed initial treatment. This is especially worrisome in the context of the pandemic, where COVID-19 positive patients must be promptly identified, isolated and contact-traced, and eluded diagnosis might possibly endanger communities and healthcare workers. We present cases of patients who initially presented with symptoms and laboratory findings of dengue fever, including positive NS1 and/or IgM serology results. During the course of illness these patients fail to show characteristic dengue symptoms, and two cases begin to show respiratory symptoms. Upon further investigation with chest X-ray or contact tracing, the patients were indicated for COVID-19 swab test, which yielded positive results. Repeat dengue IgM/IgG returned positive in one case, suggesting dengue coinfection; however in all other cases, the repeat testing returned negative, suggesting that the initial serologies were false positives. These cases highlight the importance of comprehensively studying patients with apparent dengue fever symptoms and serology, and using the appropriate adjuvant test according to the course of the disease, since a serological overlap may exist between the two diseases.