Building the Future of Immunotherapy
Why durable responses in solid tumors demand immune coordination
T cell engagers have redefined what’s possible in cancer treatment. In blood cancers, they’ve delivered rapid and meaningful responses. But in solid tumors, that success has been harder to sustain. The challenge isn’t a failure of immune cell engagement, it’s a failure of immune coordination.
T cell engagers work by linking CD3 on a T cell to a tumor-associated antigen, triggering targeted cell killing. This delivers a strong initial response. But these therapies typically provide only the first activation signal (TCR stimulation via CD3). What’s often missing are the second and third signals that are essential for sustaining and expanding a productive T cell response.
Signal 2 comes from co-stimulatory molecules like CD28, delivered by antigen-presenting cells such as dendritic cells.
Signal 3 involves cytokines like IL-15 or IL-12, which support T cell survival, proliferation, and differentiation.
Without these, CD8+ T cells often activate briefly, then rapidly exhaust, losing their ability to kill, expand, or persist.
Tumor Adaptation Demands a Smarter Immune Response
Antigen escape further complicates the picture. Solid tumors are genetically unstable and frequently downregulate or mutate the target antigen in response to therapy. A successful immune response must therefore be multi-targeted, capable of adapting alongside the tumor.
That kind of flexibility doesn’t come from a single engineered molecule. It comes from engaging the endogenous immune system, activating the body’s own T cells and dendritic cells to present, recognize, and respond to new antigens as the tumor evolves. This process, known as epitope spreading, is a critical mechanism for achieving lasting responses and preventing relapse.
Cytokine Toxicity Is Being Managed
Cytokine release syndrome (CRS) was once a limiting concern for T cell engagers. But today’s clinical protocols, featuring premedication with corticosteroids, IL-6 blockers like tocilizumab, and TNF inhibitors such as adalimumab, have made CRS increasingly manageable. Most clinicians now consider CRS a solvable challenge, not a barrier to innovation.
So the field is no longer limited by potency or safety alone. The key question is durability. Can a therapy maintain immune pressure long enough to clear the tumor, and keep it from coming back?
Structure Matters: Lessons from HCC
Our recent studies in hepatocellular carcinoma (HCC), supported by findings from other cancer types, offer valuable insight. Patients who responded to PD-1 blockade didn’t just have more T cells. They had structured immune interactions within the tumor, what we call immune triads:
Progenitor CD8+ T cells, with the potential to become potent killers
Helper CD4+ T cells, which orchestrate and amplify the response
Dendritic cells, which provide essential co-stimulation and survival cues
In these triads, CD4+ T cells and dendritic cells deliver signals 2 and 3, enabling CD8+ T cells to avoid exhaustion, differentiate into effector cells, and persist over time.
In nonresponders, these triads were absent or dysfunctional. The immune system was present but lacked the structure and communication needed for durable activity.
Adaptive and Durable Immunity Requires Coordination
In responders, these triads not only supported tumor clearance, but also likely enabled responses against multiple tumor antigens. As dendritic cells picked up and presented new antigen fragments, the immune system adapted in real time, broadening its response, overcoming escape mutations, and delivering true epitope spreading.
Helper T cells were essential to this process. They supported CD8+ differentiation, sustained cytokine production, and helped establish immune memory, the foundation for long-term tumor control. Without CD4+ help, memory formation is incomplete, and relapse is far more likely.
A New Standard for Immune Therapies
T cell engagers are powerful, but most current designs activate CD8+ T cells in isolation. Without helper T cells and dendritic cell engagement, these T cells lose steam quickly, especially in the suppressive environment of solid tumors.
Checkpoint inhibitors opened the door. T cell engagers pushed it wider. But what comes next must go beyond targeting a single receptor or antigen. It must orchestrate the full immune circuit.
The therapies that succeed in solid tumors will:
Activate T cells without triggering exhaustion
Remain effective even as the tumor evolves
Promote epitope spreading to broaden immune recognition
Establish local memory to protect against recurrence
These are no longer theoretical. They are the new standards that define success in immuno-oncology.
Final Thought
The future of T cell therapy isn’t about hitting harder. It’s about engaging smarter. The therapies that win will not only kill tumor cells—they’ll recruit, coordinate, and educate the immune system to finish the job and remember how to do it again.
For the teams building that future, and the investors backing them, the opportunity is real, and it’s here.