Author: Chuy, Jennifer ; McAuliffe, John C. ; Li, Jenny ; DesMarais, Vera ; Libutti, Steven K. ; Zhang, Xusheng ; Koba, Wade ; Patel, Ankur ; Friedman, Madeline ; Quispe-Tintaya, Wilber ; Selvanesan, Benson Chellakkan ; Khouri, Olivia ; Beck, Amanda ; Yuan, Ziqiang ; Meena, Kiran ; Condeelis, John ; Gravekamp, Claudia ; Wang, Yarong ; Gabor, Lisa ; Jahangir, Arthee ; Entenberg, David ; Lin, Ken ; Alves Da Silva, Rodrigo Alberto ; Siddiqui, Sarah ; Tesfa, Lydia ; Jafari, Rojin ; Chandra, Dinesh ; Balachandran, Vinod

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease. Tumors are poorly immunogenic and immunosuppressive, preventing T cell activation in the tumor microenvironment. Here, we present a microbial-based immunotherapeutic treatment for selective delivery of an immunogenic tetanus toxoid protein (TT 856-1313 ) into PDAC tumor cells by attenuated Listeria monocytogenes . This treatment reactivated preexisting TT-specific memory T cells to kill infected tumor cells in mice. Treatment of KrasG12D,p53R172H, Pdx1-Cre (KPC) mice with Listeria -TT resulted in TT accumulation inside tumor cells, attraction of TT-specific memory CD4 T cells to the tumor microenvironment, and production of perforin and granzyme B in tumors. Low doses of gemcitabine (GEM) increased immune effects of Listeria -TT, turning immunologically cold into hot tumors in mice. In vivo depletion of T cells from Listeria -TT + GEM–treated mice demonstrated a CD4 T cell–mediated reduction in tumor burden. CD4 T cells from TT-vaccinated mice were able to kill TT-expressing Panc-02 tumor cells in vitro. In addition, peritumoral lymph node–like structures were observed in close contact with pancreatic tumors in KPC mice treated with Listeria -TT or Listeria -TT + GEM. These structures displayed CD4 and CD8 T cells producing perforin and granzyme B. Whereas CD4 T cells efficiently infiltrated the KPC tumors, CD8 T cells did not. Listeria -TT + GEM treatment of KPC mice with advanced PDAC reduced tumor burden by 80% and metastases by 87% after treatment and increased survival by 40% compared to nontreated mice. These results suggest that Listeria -delivered recall antigens could be an alternative to neoantigen-mediated cancer immunotherapy.

Biomaterials ScienceQ2 · ENGINEERING & TECHNOLOGY

Single nanoparticles as versatile phototheranostics for tri-modal imaging-guided photothermal therapy

Q2 · ENGINEERING & TECHNOLOGY

Article

Author: Huang, Wei ; Xie, Chen ; Xu, Jingzeng ; Fan, Quli ; Xia, Bing ; Chen, Jiaqi ; Wang, Qi ; Lu, Xiaomei ; Li, Jie

Novel versatile phototheranostics have been successfully developed for tri-modal (NIR-II fluorescence/photoacoustic/thermal) imaging-guided photothermal therapy, which was triggered by a single-wavelength laser.

Immunotherapy for ovarian cancer is improved by tumor targeted delivery of a neoantigen surrogate

Author: Lin, Ken ; Kuo, Dennis Yi-Shin ; Ahmad, Shahbaz ; Levy, Evan ; Nevadunsky, Nicole ; Gravekamp, Claudia ; Gabor, Lisa ; Khouri, Olivia Richardson ; Scanlon, Lauren Rose

Ovarian cancer is known for its poor neoantigen expression and strong immunosuppression. Here, we utilized an attenuated non-pathogenic bacterium Listeria monocytogenes to deliver a highly immunogenic Tetanus Toxoid protein (Listeria-TT), as a neoantigen surrogate, into tumor cells through infection in a metastatic mouse ovarian cancer model (Id8p53-/-Luc). Gemcitabine (GEM) was added to reduce immune suppression. Listeria-TT+GEM treatments resulted in tumors expressing TT and reactivation of pre-existing CD4 and CD8 memory T cells to TT (generated early in life). These T cells were then attracted to the TT-expressing tumors now producing perforin and granzyme B. This correlated with a strong reduction in the ovarian tumors and metastases, and a significant improvement of the survival time compared to all control groups. Moreover, two treatment cycles with Listeria-TT+GEM doubled the survival time compared to untreated mice. Checkpoint inhibitors have little effect on ovarian cancer partly because of low neoantigen expression. Here we demonstrated that Listeria-TT+GEM+PD1 was significantly more effective (efficacy and survival) than PD1 or Listeria-TT+GEM alone, and that more treatment cycles with Listeria-TT+GEM+PD1 significantly increased the survival time compared to Listeria-TT+GEM alone. In summary, the results of this study suggest that our approach may benefit ovarian cancer patients.

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Indication	Highest Phase	Country/Location	Organization	Date
Pancreatic Ductal Adenocarcinoma	Preclinical	United States	Albert Einstein College of Medicine, Inc.	22 May 2023

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