When the Immune System Cannot Get In

CatalYm is developing an antibody designed to block GDF-15, a signal tumors can use to keep immune cells out and that also contributes to cancer-related wasting.

Immunotherapy changed cancer treatment by helping the immune system recognize and attack tumors. But in many patients, the problem is not only whether T cells are activated. It is whether they can physically get into the tumor and stay effective once they arrive.

Checkpoint inhibitors are often explained as taking the brakes off the immune system. The metaphor is useful, but incomplete. A car with its brakes released still cannot drive through a locked gate. Some tumors create a microenvironment that keeps immune cells at the perimeter, and tumors that once responded can become resistant.

CatalYm, a Canaan portfolio company, is built around one of those gates: a protein called GDF-15. Its lead drug, visugromab, is designed to neutralize GDF-15 so immune cells can infiltrate tumors more effectively and checkpoint therapy can resume its attack on cancer cells.regain activity. Canaan partner Colleen Cuffaro led our 2024 investment and joined the board as CatalYm moved from early clinical proof-of-concept into later stage a broader randomized clinical trials. development program.

Checkpoint inhibitors such as anti-PD-1 agentsmedicines emerged as a key clinical tool to combat became important because cancer’s ability to can quiet T cells by exploiting natural immune checkpoints. to quiet T cells. Blocking those checkpoints can restore an immune response, sometimes dramatically. But the benefits are uneven, and even tumors that initially respond can later progress.

That focus on immune activation made sense. If a tumor is suppressing the immune system, remove the suppression and let the immune cells do their job.

CatalYm is challenging a more specific assumption: that activated T cells can necessarily reach the place where they are needed. The company’s science suggests that GDF-15 can interfere with the adhesion process T cells use to move from blood vessels into tumor tissue. In plain English, the immune system may be ready to fight but blocked from engaging its target.and still be kept outside.

CatalYm grew out of research led by Professor Jörg Wischhusen at the University of Würzburg. His group studied GDF-15, a stress-response protein abundant in the placenta and many solid tumors. The connection was striking: a signal associated with immune tolerance in pregnancy also appeared capable of helping tumors avoid immune attack.

That insight led to CatalYm’s founding in 2016 and eventually to visugromab, a monoclonal antibody designed to neutralize GDF-15. CatalYm is testing whether removing this barrier can make existing immunotherapies work better.

There is a second reason GDF-15 matters. The same protein can signal through the brainstem in ways associated with loss of appetite, weight, and muscle in cancer cachexia. That gives CatalYm an unusual therapeutic thesis: one target may sit at the intersection of two different problems, resistance inside the tumor and physical decline across the rest of the body.

The larger question remains unproven, but the idea has moved well beyond laboratory biology.

In 2024, results from CatalYm’s first-in-human Phase 1/2a study were published in Nature. In heavily pretreated patients whose cancers had progressed after checkpoint therapy, some experienced deep, durable responses with visugromab plus nivolumab. The study also found biological evidence of increased T-cell infiltration and activity inside tumors.

CatalYm has since moved into more rigorous testing. In an exploratory randomized Phase 2 bladder cancer study presented at ESMO 2025, the pathological complete response rate was 33.3% with visugromab plus nivolumab versus 7.1% with nivolumab alone. By 2026, the company had randomized Phase 2b clinical trials underway programs in lung and liver cancers, plus a Phase 2/3 study testing visugromab directly in cancer cachexia.

The answer is not settled. What matters is that CatalYm is now testing whether GDF-15 blockade can work earlier, across multiple settings, and against more than one consequence of cancer.

When Canaan led CatalYm’s $150 million Series D in 2024, Colleen publicly pointed to two things that stood out: the differentiated therapeutic profile emerging in the clinical data and the team’s ability to execute as it prepared for broader Phase 2b development.

Interesting biology is common in biotech. What is harder to find is a distinct, clinically testable mechanism with enough human evidence to justify a much larger question. CatalYm had reached that point with GDF-15.

The significance was not simply another oncology drug. It was the possibility that some immunotherapy resistance could be understood as an access problem, and that removing the barrier might reopen a treatment path that appeared to have closed.

Cancer resistance becomes personal quickly. A therapy works, then stops. A patient loses weight and strength. The next treatment becomes harder to tolerate.

If GDF-15 contributes both to keeping immune cells out of tumors and to the wasting that can accompany advanced cancer, blocking it could affect more than a scan. It could potentially influence whether treatment keeps working and how well a patient can withstand the disease and its therapy.

The question CatalYm is asking is not simply whether blocking one protein can make checkpoint inhibitors work better. It is whether cancer treatment can become more effective by dismantling the protective environment a tumor builds around itself, while easing one of the body’s most punishing responses to advanced disease.

That points toward a broader way of thinking about resistance. A treatment that stops working may not have reached an absolute biological limit. There may be another barrier in the way. If CatalYm can validate GDF-15 as one of those barriers in larger randomized studies, the company could help turn resistance from a treatment hurdlen endpoint into a problem with another lever.