Reza Assaran Darban’s Post

#NatureBiotechnology: A CAR enhancer increases the activity and persistence of CAR T cells Although chimeric antigen receptor (CAR) T cell therapies have demonstrated promising clinical outcomes, durable remissions remain limited. To extend the efficacy of CAR T cells, we develop a CAR enhancer (CAR-E), comprising a CAR T cell antigen fused to an immunomodulatory molecule. Here we demonstrate this strategy using B cell maturation antigen (BCMA) CAR T cells for the treatment of multiple myeloma, with a CAR-E consisting of the BCMA fused to a low-affinity interleukin 2 (IL-2). This selectively induces IL-2 signaling in CAR T cells upon antigen–CAR binding, enhancing T cell activation and antitumor activity while reducing IL-2-associated toxicities. We show that the BCMA CAR-E selectively binds CAR T cells and increases CAR T cell proliferation, clearance of tumor cells and development of memory CAR T cells. The memory cells retain the ability to re-expand upon restimulation, effectively controlling tumor growth upon rechallenge. Mechanistic studies reveal the involvement of both CAR and IL-2 receptor endodomains in the CAR-E mechanism of action. The CAR-E approach avoids the need for specific engineering and enables CAR T cell therapy with lower cell doses. https://lnkd.in/gg54gX5B

#Solid tumors have posed a formidable challenge for #immunotherapies. #TCR-based therapies can specifically target and destroy solid tumor cells with unprecedented #precision and open new avenues for personalyzed medicine and more importantly for #patients looking for new therapeutic avenues. We at Affini-T Therapeutics along with others in the field aim to turn the tide in the battle against #cancer. #TCRTherapies #InnovationMedicine #HopeForPatients

Just published in #NatureBiotechnology, comprehensive list of engineered TCR-T cell therapy in clinical trials for #SolidTumors and the expectation. TCR cell therapies vanquish solid tumors — finally - Nature Portfolio The FDA’s approval of the first genetically modified T cell therapy for treating a rare sarcoma is paving the way for next-generation therapies that tackle other types of solid tumors. The US Food and Drug Administration has granted accelerated approval to Adaptimmune’s Tecelra (#AfamitresgeneAutoleucel), making it the first engineered T cell therapy to gain approval for a solid tumor indication. The green light for synovial sarcoma, announced in July, follows the approval earlier this year of a non-engineered T cell immunotherapy, Iovance Biotherapeutics, Inc.’s #Amtagvi (#lifileucel), which infuses a person’s own tumor-infiltrating lymphocytes (TIL) to treat advanced melanoma. Both treatments harness the T cell receptor (#TCR) on lymphocytes to recognize and attack tumors, but the long and difficult manufacture of TILs mean that many biotechs are looking toward TCR-T cells. https://lnkd.in/efZ6pRBp

TCR Cell therapies vanquish solid tumors

📰 INDIGO In Action 📰 This recent publication titled "Preclinical Characterization of Linrodostat Mesylate, a Novel, Potent, and Selective Oral Indoleamine 2,3-Dioxygenase 1 Inhibitor" utilizes INDIGO's AhR assay kit! "Linrodostat mesylate (linrodostat) is a potent, selective oral IDO1 inhibitor that occupies the heme cofactor-binding site to prevent further IDO1 activation and is currently in multiple clinical trials for treatment of patients with advanced cancers. Here, we assess the in vitro potency, in vivo pharmacodynamic (PD) activity, and preclinical pharmacokinetics (PKs) of linrodostat." Read now by clicking on the link below 🎉 https://bit.ly/4fA8Hfp

Yuheng Gu and Qi Zhao provide a comprehensive review of the recent advances in the development and clinical application of bispecific antibodies (BsAbs) for the treatment of solid tumors. They discuss the different formats, the unique mechanisms of action, and the clinical outcomes of the most advanced BsAbs in development.

📚 Major Histocompatibility complex is a set of genes located on chromosome 6 that play a crucial role in the immune system. While important, it is is difficult to study due to the genetic diversity. 🚀 Good to hear about the MHCepitopes database which contains 451,065 MHC peptide epitopes!

In this preclinical report, U Penn scientists show that CD5 deletion enhances the potency of CAR-T and TCR-T in a wide range of mouse models entailing hematologic or solid tumors, with or without a competent endogenous immune system. The anti-tumor potency with CD5 deletion was found to be greater than with SHP1 or PD1 deletion. RNA sequencing analyses of CD5 KO T cells, TCGA tumor samples, and real world tisa-cel and axi-cel clinical data sets support the hypothesis that CD5 dampens T cell effector functions. CD5 deletion did not manifest increased safety risks in standard preclinical toxicology assays mandated by the FDA. To enable clinical development, the authors developed a 5-day-long manufacturing process with Cas9/CD5 gRNA RNP electroporation and lentiviral transduction, which led to greater potency as compared with their prior manufacturing protocol. A phase 1 study of the CD5 KO CAR-T is being initiated to treat CD5+ r/r TCL. https://lnkd.in/eD4D7NmK

𝐁𝐢𝐨𝐡𝐲𝐛𝐫𝐢𝐝 𝐦𝐢𝐜𝐫𝐨𝐫𝐨𝐛𝐨𝐭𝐬 𝐥𝐨𝐜𝐚𝐥𝐥𝐲 𝐚𝐧𝐝 𝐚𝐜𝐭𝐢𝐯𝐞𝐥𝐲 𝐝𝐞𝐥𝐢𝐯𝐞𝐫 𝐝𝐫𝐮𝐠-𝐥𝐨𝐚𝐝𝐞𝐝 𝐧𝐚𝐧𝐨𝐩𝐚𝐫𝐭𝐢𝐜𝐥𝐞𝐬 𝐭𝐨 𝐢𝐧𝐡𝐢𝐛𝐢𝐭 𝐭𝐡𝐞 𝐩𝐫𝐨𝐠𝐫𝐞𝐬𝐬𝐢𝐨𝐧 𝐨𝐟 𝐥𝐮𝐧𝐠 𝐦𝐞𝐭𝐚𝐬𝐭𝐚𝐬𝐢𝐬. Lung metastasis poses a formidable challenge in the realm of cancer treatment, with conventional chemotherapy often falling short due to limited targeting and low accumulation in the lungs. Here, a microrobot approach using motile algae for localized delivery of drug-loaded nanoparticles is shown to address lung metastasis challenges. The biohybrid microrobot [denoted “algae-NP(DOX)-robot”] combines green microalgae with red blood cell membrane–coated nanoparticles containing doxorubicin, a representative chemotherapeutic drug. Microalgae provide autonomous propulsion in the lungs, leveraging controlled drug release and enhanced drug dispersion to exert antimetastatic effects. Upon intratracheal administration, algae-NP(DOX)-robots efficiently transport their drug payload deep into the lungs while maintaining continuous motility. This strategy leads to rapid drug distribution, improved tissue accumulation, and prolonged retention compared to passive drug-loaded nanoparticles and free drug controls. In a melanoma lung metastasis model, algae-NP(DOX)-robots exhibit substantial improvement in therapeutic efficacy, reducing metastatic burden and extending survival compared to control groups. https://lnkd.in/g3GQGMqS

Exposure time matters! I highly recommend reading another work of Evans et al., “Exposure Time versus Cytotoxicity for Anticancer Agents” (DOI: 10.1007/s00280-019-03863-w). This study highlights how the selection of exposure time in assays can significantly impact the results (https://lnkd.in/eHykSy_H).