Dual-vaccine approach shows promise against T cell lymphoma

T cell lymphomas are among the toughest blood cancers to treat. Immunotherapy, despite its success in many cancers, struggles here because it can’t easily distinguish malignant T cells from healthy ones. Now, researchers at The Wistar Institute have developed a two-vaccine strategy that not only targets the tumour’s unique molecular markers but also anticipates the cancer’s evasion tactics. Their findings [1], published in Cancer Immunology, Immunotherapy, show that combining a vaccine against T cell receptors (TCRs) with a second targeting tumour-specific mutations can significantly improve tumour control and survival in preclinical models.

T cell lymphomas (TCLs) make up roughly 10% of non-Hodgkin’s lymphomas and carry a grim prognosis. Patients who relapse early after treatment face a five-year survival rate of just 11%. Unlike solid tumours or B cell cancers, TCLs are harder to target because the cancer arises from the very immune cells designed to fight disease. Effective therapy requires precision: targeting malignant T cells while sparing healthy ones.

The Wistar team, led by David B. Weiner, PhD, Executive VP of The Wistar Institute and Director of Wistar’s Vaccine & Immunotherapy Center, together with first author Pratik S. Bhojnagarwala, PhD, postdoctoral fellow in the Weiner Lab, identified a critical weakness in T cell cancers: clonality. Each cancerous T cell is a clone, displaying the same TCR ‘fingerprint’ on its surface - offering a precise therapeutic target.

“As a T cell becomes cancerous, all the new cells carry the same receptor,” said Bhojnagarwala. “This allows us to design vaccines that attack the cancerous TCR while leaving healthy T cells untouched.”

Using Wistar’s synDNA neoantigen platform in collaboration with Geneos Therapeutics, the team created TCRfullvax, a synthetic DNA vaccine encoding all three TCR chains expressed in a murine T cell lymphoma model, EL4. The vaccine triggered strong immune responses against all three chains, selectively targeting cancer cells without harming healthy T cells. TCRfullvax slowed tumour growth and improved survival, but over time, tumour cells downregulated their TCRs to evade detection.

To counter this, the researchers developed EL4neovax, a second vaccine targeting 15 tumour-specific neoantigens - mutated proteins absent from healthy cells. EL4neovax elicited robust responses against five neoantigens and independently controlled tumour growth.

Administering both vaccines together amplified the effect: combination therapy outperformed either vaccine alone, delivering superior tumour control and prolonged survival. “Using both vaccines together kills more cancer cells upfront and leaves the tumour less time to adapt or hide,” said Bhojnagarwala.

The study builds on Wistar’s established synDNA platform, previously shown to encode up to 40 distinct neoantigens simultaneously. “This research highlights the expanding potential of neoantigen immunotherapy,” said Weiner. “It’s about matching treatments to each patient’s unique cancer profile and improving outcomes with next-generation precision tools.”

Funding: Geneos Therapeutics; W.W. Smith Charitable Trust; Jill and Mark Fishman Foundation; Inovio Pharmaceuticals; Cancer Center Support Grant P30 CA010815.

More information online

SynDNA Vaccine Against TCR Chains and Neoantigens for T Cell Lymphoma Therapy published in Cancer Immunology, Immunotherapy, 2026. Online publication.