Currently Viewing:
Newsroom
Currently Reading
AHIP Packages Healthcare Affordability Recommendations; ACA Enrollment Dips
November 14, 2018 – Allison Inserro
Higher BMI Decreases Risk of Breast Cancer in Premenopausal Women
November 14, 2018 – David Bai, PharmD
Provider Stigma Toward HIV Slows Prevention Goals
November 14, 2018 – Jaime Rosenberg
Most Patients With CF May Get Insufficient Antibiotics to Fight Lung Infections
November 14, 2018 – Jackie Syrop
Common Probiotic Stimulates Bone Formation in Mice, Study Says
November 14, 2018 – Allison Inserro
What We're Reading: Wildfire Health Emergency; New Express Scripts Formulary; Insurer Monopoly in Florida
November 14, 2018 – AJMC Staff
Which Patients With COPD Are Affected the Most by Extreme Weather?
November 14, 2018 – Allison Inserro
ANCHOR Study Finds High Adherence Rate in Patients With Hepatitis C Who Inject Opioids
November 13, 2018 – Surabhi Dangi-Garimella, PhD
Hoping to Fend Off FDA, Juul to Stop Selling Certain e-Cig Flavors, For Now
November 13, 2018 – Allison Inserro

Switchable CAR T Cells May Be Safer in Pancreatic Cancer

David Bai, PharmD
Switchable chimeric antigen receptor (CAR) T cells with a switch directed towards human epidermal growth factor receptor 2 (HER2) in pancreatic ductal adenocarcinoma (PDAC) has similar efficacy as conventional HER2 CAR T cells while also having a greater control over treatment toxicities.
Switchable chimeric antigen receptor (CAR) T cells with a switch directed towards human epidermal growth factor receptor 2 (HER2) in pancreatic ductal adenocarcinoma (PDAC) has similar efficacy as conventional HER2 CAR T cells while also having a greater control over treatment toxicities.

PDAC is the fourth leading cause of cancer-related deaths, with less than 20% of patients having resectable tumors. While CAR T-cell treatments have shown substantial efficacy in hematological malignancies, outcomes in solid tumors such as pancreatic cancer have been limited. Further, since the antigen is expressed on tumors as well as normal tissue, CAR T-cell toxicities can affect healthy organs as well. Attempts are currently being made to create “switchable” CAR T cells whose activity can be titrated in vivo so that they are more specific toward tumors. Allowing CAR T cells to bind a peptide specifically onto a tumor-binding Fab molecule creates a bridge that can connect the target tumor and effector T-cells, thereby regulating treatment and enhancing safety. 

In their study published in Gut, Raj et al used CAR T cells drawn from patients with stage IV PDAC to determine if switchable CAR T cells have comparable efficacy as conventional CAR-T cells while targeting HER2, a viable target in PDAC. When comparing conventional CAR-T cells with switchable CAR-T cells, both were able to induce cytotoxicity in HER2-expressing PDAC cells. In addition, when an inactive switch of a wild-type HER2 Fab was placed, there was no cytotoxic effect on PDAC cells, identifying the importance of the switch. 

To further examine the effectiveness of CAR T cells in PDAC, investigators created a microenvironment of cancer stem cells—a physical barrier for T cell connection with tumor cells in vitro. Following a few days of culture, CAR T-cell activity was observed in both treatment groups, marked by increased T cell proliferation and enhanced production of the cytotoxic molecule granzyme B. 

Subsequent studies evaluated the efficacy of HER2 CAR T and switchable CAR T cells in vivo. Immunocompromised mice were implanted with patient PDAC cells and treated with both types of CAR T-cell therapy. Non-invasive bioluminescence imaging of the mice showed reduced tumor growth by day 3 and tumors disappeared by day 10 as. However, mice that had received no treatment or CAR T-cell treatment with an inactive switch continued to progress. 

The efficacy of switchable CAR T and conventional CAR T therapy were also compared through dose titrations. Similar tumor regression was observed in both treatment groups, with similar interferon and tumor necrosis factor cytokine release at each T cell dose, with the exception that IL-2 was higher in the conventional CAR-T cell group. 

Finally, when comparing conventional CAR T with switchable CAR T-cell therapy in disseminated metastasis, rapid tumor clearance was observed in both treatment groups. The mice treated with either therapies remained tumor free for the remainder of the study, which was 5 months following T cell administration. From these mouse models, it seems that switchable CAR T therapy can be effectively used to treat PDAC even in the more advanced cases, while also having a better safety profile than conventional CAR-T therapy.

Reference

Raj D, Yang M, Rodgers D, et al. Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma [published online August 18, 2018]. Gut.doi: 10.1136/gutjnl-2018-316595.

Related Articles

Rucaparib May Have Potential Clinical Benefit for Advanced Pancreatic Cancer
Single Resistant Cell Causes Case of Rare ALL Relapse After CAR T Therapy
Researcher Looks Ahead to Future Improvements in CAR T
 
Copyright AJMC 2006-2018 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
x
Welcome the the new and improved AJMC.com, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up
×

Sign In

Not a member? Sign up now!