Big Pharma Sharma

Big Pharma Sharma

Share this post

Big Pharma Sharma
Big Pharma Sharma
Flipping the Script on Failed Immuno-Oncology Targets: The Case for “Inverse-I/O” in Autoimmune Diseases

Flipping the Script on Failed Immuno-Oncology Targets: The Case for “Inverse-I/O” in Autoimmune Diseases

Big Pharma Sharma's avatar
Big Pharma Sharma
Oct 28, 2024
∙ Paid
2

Share this post

Big Pharma Sharma
Big Pharma Sharma
Flipping the Script on Failed Immuno-Oncology Targets: The Case for “Inverse-I/O” in Autoimmune Diseases
2
Share
Figure 1: Dempke et. al, European Journal of Cancer, March 2017

Since the success of PD-(L)1 therapies, immuno-oncology (I/O) has been a hotbed of activity, with companies scrambling to find the next blockbuster target. But for every success story, there’s a long list of targets that just didn’t work out in oncology, like IDO, 4-1BBL, OX40, and CD40. While these targets didn’t pan out in cancer, they may hold untapped potential if we “flip the script” and explore their inverse mechanisms—targeting them not to stimulate, but to suppress immune activity in autoimmune diseases.

Interested in advertising?

The Cancer-Autoimmune Axis

Figure 2: Sakowska et. al, Frontiers in Immunology, May 2022

Cancer and autoimmune diseases are almost opposites in terms of immune activity. In cancer, the immune system is underactive, and drugs like PD-1 inhibitors work by removing the brakes on T-cell activity to help the immune system attack cancer. In autoimmune diseases, the immune system is overactive, so the goal is to rein in immune responses, often by blocking pro-inflammatory pathways or activating anti-inflammatory ones. This dynamic suggests that previously unsuccessful oncology targets could be re-engineered to shut down, rather than stimulate, the immune response—providing a potential breakthrough in autoimmune and inflammatory diseases.

Inverse-I/O in Action: CD40L and OX40L

The table below illustrates two promising “inverse-I/O” examples: CD40L and OX40L. Both targets failed in the oncology context but are now gaining traction in autoimmune diseases, with multiple Phase 3 trials in progress. These trials highlight how leveraging the inverse mechanisms of failed I/O targets may open up new therapeutic pathways in autoimmune and other diseases.

To read this full post and unlock all my past posts, I urge you to become a paid subscriber for just $10/month (or less if you buy the full year upfront).

Keep reading with a 7-day free trial

Subscribe to Big Pharma Sharma to keep reading this post and get 7 days of free access to the full post archives.

Already a paid subscriber? Sign in
© 2025 Big Pharma Sharma LLC
Privacy ∙ Terms ∙ Collection notice
Start writingGet the app
Substack is the home for great culture

Share