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Nicholas P. Restifo: Anti-CTLA-4 Induces Stronger Immune Memory Than Anti-PD-1

Nicholas Restifo/LinkedIn

Jan 30, 2025, 19:22

Nicholas P. Restifo: Anti-CTLA-4 Induces Stronger Immune Memory Than Anti-PD-1

Nicholas P. Restifo, Co-Founder and Chief Medical Officer, Medici Therapeutics; Managing Partner, RestifoPartners, LLC, shared a post on LinkedIn:

“Anti-CTLA-4 Induces Stronger Immune Memory Than Anti-PD-1

Immune checkpoint blockade (ICB) has transformed cancer therapy, and anti-CTLA-4 and anti-PD1 have profoundly changed the landscape of cancer research, but they work by entirely different mechanisms. A recent study from James Allison and colleagues shows in an elegant mouse model that anti-CTLA-4 generates a greater memory response than anti-PD1.

What is the clinical evidence that this is the case?

We observed that prior treatment with anti-CTLA-4 enhanced TIL-based treatments with a-CTLA-4

Nicholas P. Restifo: Anti-CTLA-4 Induces Stronger Immune Memory Than Anti-PD-1

Conversely, prior treatment with a-PD1 profoundly depressed the ability of TIL-based therapies to mediate melanoma-specific survival in patients.

Jim and colleague’s new work explains mechanistically why this is the case:

Key Findings:

– Anti-CTLA-4 generates stronger immune memory than anti-PD-1 by preserving TCF-1+ CD8+ T cells, which are critical for long-term response.

– CD4+ T cells are essential for anti-CTLA-4-driven memory but not for anti-PD-1.

– Memory T cells from anti-CTLA-4-treated mice showed enhanced IFNγ production and tumor control upon rechallenge.

– Chronic antigen stimulation was ruled out as the key driver—suggesting fundamental differences in how checkpoint inhibitors shape immunologic memory.

Why Does This Matter?

These results highlight mechanistic differences between CTLA-4 and PD-1 blockade, offering insights into why some checkpoint therapies induce long-lasting responses while others do not. This understanding is critical for designing next-generation immunotherapies with improved durability. We found that TCF-1+ T cells are the long sought after ‘T memory stem cells in mice and in humans.

What’s Next?

Further research into the transcriptional and functional differences between T cells responding to checkpoint blockade may open doors to combination strategies that optimize immune memory and enhance cancer immunotherapy outcomes.

What are your thoughts on these findings? Do they align with what you’ve observed in checkpoint blockade therapy? Let’s discuss!”

Nicholas P. Restifo: Anti-CTLA-4 Induces Stronger Immune Memory Than Anti-PD-1