For years, all available data and our understanding of immune physiology suggested that γδ T cells were especially equipped to generate a robust immune response against cancer. Yes, they are typically very scarce, but that meant they simply need to be expanded.
In order to clear cancer that has spread, a therapy must be able to detect and kill cancer cells that have evaded the immune system. γδ T cells are capable of killing cancer cells because of a combination of abilities that other immune cells do not possess. They recognize signals of stress or damage common to most cancerous cells, generate potent cytotoxicity through granzyme and perforin production, enabling them to detect and kill cancer cells independent of antigen-based mechanisms. Simultaneously, they orchestrate a broad immune response that can take advantage of newly released antigens to search for and destroy other cancer cells, resulting in the kind of comprehensive, robust immune response that is expected to eliminate tumors.
Despite multiple attempts to develop γδ T cell therapies, almost nothing has improved patient outcomes. We may finally know why, and the answer may be the key to unlocking the therapeutic potential of γδ T cells and expanding immunotherapy where it has struggled or failed.
Suspect #1, the Scarcity of γδ T cells
The first, most obvious theory was the one scientists and clinicians already believed. γδ T cells circulate at such low frequency that most of oncology had quietly filed them away as a footnote. Monoclonal antibodies and T-cell engagers are targeting technologies; they tell the immune system where to attack, but they don’t generate more attackers, and if there simply aren’t enough functional effector cells present to begin with, then precision targeting cannot evoke an effective response. This logic explains, reasonably well, why so many antibody and engager programs underperform in solid tumors, where infiltrating T cell numbers are often vanishingly small.
So the fix seemed obvious: expand the population of γδ T cells. Zoledronic acid is a bisphosphonate drug that drives γδ T cell proliferation by inhibiting a specific step in the mevalonate pathway. Cancer patients have been dosed with zoledronic acid for decades. The innate γδ T cells would reliably multiply, often significantly, and yet almost nothing changed for these patients. The cells were there in force, but they weren’t effective and didn’t persist. For many immunologists and drug developers, this was ‘case closed’ on γδ T cells. If scarcity were the whole story, this should have worked, but it didn’t.
Researchers knew there are many types of γδ T cells, so perhaps zoledronic acid was simply expanding the wrong type.
Suspect #2, Find the Correct γδ T cells
Perhaps the problem wasn’t quantity at all, but precision. Zoledronic acid expands the Vδ2 subset of γδ T cells, which circulate systemically and may penetrate tissue and solid tumors. Many researchers turned their focus to the Vδ1 subset of γδ T cells, which naturally reside within tissues and have been a positive prognostic indicator when found inside tumors. Takeda, Adicet, and others generated T cell engagers that specifically bound to the Vδ1 receptor, or CAR-γδ T cells that express Vδ1. The rationale was simple, if Vδ2 T cells were underwhelming, perhaps Vδ1 T cells might be the solution. However, the general scarcity problem of γδ T cells is even more acute for Vδ1 T cells, and there are no known drugs that specifically expand Vδ1 T cells. The hope was that T cell engagers (TCEs) would not just activate, but also expand Vδ1 T cells, or that enough CAR-γδ T cells that express Vδ1 could be generated ex vivo. Unfortunately, these efforts were also largely unsuccessful. Among many other factors, TCEs did not expand Vδ1 T cells, and while the CAR-γδ T cells developed by Adicet and others are showing promising clinical results, they are limited by the same complications and complexities as other allogeneic CAR-T therapies.
While others were working on the Vδ1 subset of γδ T cells, researchers throughout academia and at companies like ImCheck, and ourselves at Laguna continued to study the Vδ2 subset because we observed their undeniable cytotoxic effects against cancer cells in vitro, and publications of investigator-led clinical studies were showing promising results even when large numbers of unmodified γδ T cells were adoptively transferred into cancer patients. This work indeed led to a breakthrough in January 2026 when ImCheck’s ICT01 therapy was granted FDA Breakthrough Therapy Designation in relapsed/refractory acute myeloid leukemia (R/R AML), providing recognition by regulatory bodies of clinical data that drove Ipsen’s prior acquisition of the program. ICT01 is an agonist antibody against BTN3A1, one of the most potent known activators of Vδ2 T cells. ICT01 locks BTN3A1 into an activated conformation, marking stressed and malignant cells for γδ T cell-mediated killing.
The results were striking: in adult R/R AML patients who already had sufficient endogenous γδ T cells, ICT01 showed encouraging early signs of meaningfully improving complete response relative to those seen in historical standard of care data and resulted in Ipsen acquiring ImCheck in 2025 for €350M plus downstream payments up to $1B, contingent upon regulatory and sales milestones.
“As head of antibacterial discovery and then head of US west coast BD&L, I spent more than 20 years evaluating technologies for partnering and closing many inbound and outbound deals. Ipsen’s acquisition of ImCheck signaled to the biopharma ecosphere that γδ T cell biology has real therapeutic potential for AML patients. What strikes me about Laguna is that, by developing a completely unique modality that generates abundant AND active T cells, they are enabling both components necessary for the γδ T cell therapeutic approach.” -- Jennifer Leeds, PhD., former Executive Director at Novartis and Business Development Strategy Advisor to Laguna.
For the first time, a γδ T cell therapy demonstrated clear clinical benefit. Importantly, the ICT01 results are not evidence that precision targeting was the missing ingredient. They are evidence that γδ T cells work when there happen to be enough of them already present. ICT01 did very little to solve the underlying scarcity problem; it simply documented, convincingly, that abundance plus proper direction is a winning combination when this occurs naturally in a patient and does not require zoledronic acid for γδ T cell expansion. For the majority of patients who don’t start with a large enough endogenous γδ T cell population, an antibody cannot recruit cells that aren’t already there. These results are early but very strong evidence that having enough γδ T cells can absolutely transform outcomes for cancer patients. They also highlight an obvious question, why haven’t zoledronic acid-expanded γδ T cells been successful at halting cancer?
Closing the Net on the Real Culprit: A Coupling No One Had Noticed
A detailed and well-executed study published in 2025 by Suen and colleagues sheds light on the answer. Recall that zoledronate inhibits a key step in the mevalonate metabolic pathway resulting in accumulation of isoprenoids that drive γδ T cell proliferation. Suen and colleagues demonstrated that those isoprenoids must flow down that metabolic pathway to generate functional effector cytokine production. The same pathway that had to be blocked to get expansion simultaneously destroyed the cells’ capacity to then kill cancer cells. With zoledronate, expansion and inactivation of effector function aren’t two separate problems that happen to co-exist. They are two mechanistically inseparable activities of a single small molecule drug.
This reframes the entire story of the therapeutic failures of γδ T cells. The field hadn’t failed to find a sufficient expansion drug, or a precise enough targeting antibody. It had been trying to generate an abundance of functional γδ T cells using a tool that could only deliver abundant γδ T cells at the expense of their function. No amount of refinement to an antibody was going to close the activation gap created by zoledronic acid.
A Familiar Microbe is the Key to Unlocking Powerful γδ T cell Expansion & Activation
If neither small molecule expansion nor antibody-directed engagement could deliver both expansion and activation at once, the question became whether anything could; the answer lies with a microbe that has co-evolved with humans for millennia. In humans, γδ T cells have evolved to specifically expand and activate upon recognition of infection by intracellular viral and bacterial microbes such as CMV, HIV, Mycobacterium tuberculosis, and Listeria monocytogenes. Listeria monocytogenes is among the most well-studied pathogens that interact with γδ T cells, and researchers have developed precise and powerful tools for modifying L. monocytogenes to render them safe while still generating therapeutically powerful γδ T cell responses.
The mechanism, now understood at a molecular level, explains why an attenuated and non-pathogenic strain of L. monocytogenes succeeds at expanding functional γδ T cells where pharmacology alone had not. As Listeria infect host cells, they generate large amounts of microbial HMBPP, a phosphoantigen structurally distinct from, and far more potent than, the endogenous isoprenoid phosphoantigens targeted by zoledronic acid. Similar to ICT01, HMBPP binds the intracellular domain of BTN3A1, locking the receptor into a conformation sensed extracellularly by the Vγ9Vδ2 T-cell receptor, directly triggering activation. Crucially, Listeria never disrupt γδ T cell metabolism when generating expansion. γδ T cells have evolved to respond most strongly to the phosphoantigen produced by Listeria. In fact, HMBPP is likely feeding the metabolic pathway that is destroyed by zoledronic acid, resulting in enhanced γδ T cell cytokine production and cytotoxic potential.
Furthermore, Listeria do something that small molecules or biologics could not. Their bacterial components are simultaneously sensed by innate pattern-recognition pathways, driving antigen-presenting cells to produce IL-12, IL-15, IL-18, and others the exact complementary signals necessary to elicit durable proliferation and functional maturation, rather than the transient, exhaustion-prone activation that results from phosphoantigen exposure alone. Direct phosphoantigen sensing, paired with innate cytokine costimulation is a combination of signals, precisely delivered in the context that our immune system has evolved to detect. No synthetic small molecule or biologic has been able to compete with the precision and sensitivity selected during millennia of evolution.
A Completely Novel Immunotherapy
At Laguna we’ve developed the attenuated L. monocytogenes strain LGNA-100. This strain cannot cause infection because it cannot grow, replicate, or survive outside of immune cells, but it can still be recognized by endogenous γδ T cells, resulting in their expansion and activation. As a result of these attenuations, we have generated a living bacterial therapeutic that has the predictable dosing and clearance of a small molecule or biologic drug, with incomparable power to expand and activate the endogenous immune system to fight against cancer cells. To our knowledge, no approach prior to LGNA-100 has been shown to accomplish both endogenous expansion and proper functional activation of γδ T cells, unlocking a powerful new type of immunotherapy that we will evaluate in clinical studies this year.
“Previous strains of attenuated Listeria carried a serious risk of extracellular growth which could lead to rare cases of persistence. The QUAIL platform, and LGNA-100, was specifically designed to remove this risk and cannot grow extracellularly. In addition to a safer strain, our lab has developed an extensive toolkit and the molecular biological expertise for modifying Listeria to engage the immune system in precise, and deliberate ways. We currently have constructed a suite of strains in the QUAIL background that range in the capacity to induce multiple innate T-cell populations.” -- Dan Portnoy, PhD Distinguished Professor of Molecular & Cell Biology and Plant & Microbial Biology at the University of California, Berkeley, and Laguna co-founder.
In some settings, properly expanded and activated γδ T cells may be a powerful new immunotherapy that can change the outcomes for patients who desperately need effective therapy. Clinical data from pediatric post-HSCT patients treated by Dr. Bertaina showed that increased numbers of endogenous γδ T cells are independently associated with improved survival and are naturally enriched in patients who achieve durable remission. Until now there was no reliable, scalable way to reproduce this expansion in people without naturally high numbers of endogenous γδ T cells. If LGNA-100 can durably expand cytotoxic γδ T cells in a patient, without the requirement for exogenous manufacturing, the implication is a therapy that generates a strong anti-leukemic response in the setting of a disease where relapse remains the dominant cause of death.
Success as a Monotherapy Unlocks Broad Potential for Combinations Throughout Oncology
Comprehensive pre-clinical data for the CD33 x γδ TCR TCE was presented at ASH in 2024 and other recent oncology meetings. These results demonstrate that γδ T cells can locate and kill CD33-expressing AML blasts while sparing healthy CD33-expressing myeloid stem cells, even though the antibody engages CD33 on both cell types. The equivalent CD3-based engager, redirecting conventional αβ T cells, elicits more on-target, off-tumor killing of the same CD33-expressing myeloid stem cells. This is a potentially massive advance for AML patients who have not yet benefited from revolutionary immunotherapy drugs. These results support a hypothesis that has motivated γδ T cell researchers to continue their pursuit. These T cells require a genuine stress signature, not just antigen engagement, before they execute a full cytotoxic program. This results in a built-in safety architecture that conventional CD3 T cell engagers don’t display. Properly activated γδ T cells aren’t just more abundant effectors. They may be safer in a way that unlocks immunotherapy for many patients.
Enabling both γδ T cell expansion and activation changes what’s possible, even beyond monotherapy. LGNA-100-expanded γδ T cells should be better substrates for T cell engagers, especially those that specifically bind to the γδ TCR, for BTN3A agonists like ICT01, and for adoptively transferred CAR-γδ T cell products.
Immunotherapy Doesn’t Lack a Compass, It Lacks a Crew
Researchers have spent decades getting remarkably precise about where to point the immune system. We have not, until now, had a way to make sure enough of the right cells are properly activated and ready to do the work once they arrive. A well-studied pathogen, deliberately weakened and repurposed, may unlock powerful T cell expansion and activation, transforming patient outcomes across oncology.
