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Unconventional γδ T cells ‘the new black’ in cancer therapy

A new era of cancer immunotherapy beckons as γδ T cell trials enter final stage.

The unique antitumor characteristics of γδ T cells are being put to the test in a first-of-its-kind clinical study that may pave the way to a new class of immunotherapy. In the coming weeks, TC BioPharm will begin administering its proprietary formulation of donor-derived γδ T cells to patients with acute myeloid leukemia (AML) as part of a late-stage, pivotal trial designed to evaluate whether these ‘unconventional’ lymphocytes can specifically recognize cancers and rally an immune response against them — even without the addition of chimeric antigen receptors (CARs) or other types of genetic manipulation.

γδ T cells can kill hematological and solid tumors. Adapted with permission from B. Silva-Santos, K. Serre & H. Norell, Nat. Rev. Immunol. 15, 683–691 (2015), Springer Nature.

The trial should provide “proof of principle of whether it will feasible to use these off-the-shelf products,” says hematologist Emma Nicholson, a site investigator at the Royal Marsden Hospital in Sutton, UK. “There’s a lot of interest in whether γδ T cells have got antitumor activity.” Today, more than a dozen different companies are pushing ahead with γδ T cell–based therapies of their own — and so, if TC BioPharm succeeds with its therapy, many others could soon follow.

That therapy, termed OmnImmune, takes advantage of a peculiarity of γδ T cells, an immune population that combines both innate and adaptive features. Unlike most T lymphocytes, these cells carry T cell receptors (TCRs) composed of γ and δ chains, which recognize antigens without depending on major histocompatibility complex (MHC) molecules. This characteristic sets the approach apart from other T cell immunotherapeutic strategies built around more classic αβ cells, which are restricted to recognize MHC-bound peptides that go through the usual antigen processing and presentation pathways. And it allows the creation of ‘universal’ γδ T cells treatments — sourced from the blood of healthy individuals, then expanded, activated and purified — without the complicating risk of graft-versus-host-disease that necessitates further genetic engineering to make allogeneic αβ T cell therapies feasible.

“This is a population of cells that can have strong antileukemia activity,” says Alice Bertaina, a pediatric stem cell transplant specialist at Stanford University, who is not involved in the TC BioPharm trial. “The γδ T cells, even when not engineered with CARs — so, without specific targets — have the potential of mediating much more graft-versus-tumor effects than αβ T cells.”

Some companies are engineering γδ T cells nonetheless, equipping their therapies with CARs for enhanced tumor targeting and killing efficiency (Table 1). Adicet Bio, for example, incorporated a CD20-directed CAR into its lead candidate, ADI-001, which is designed to combat B cell lymphomas. According to clinical data announced in December 2021, the therapy yielded several complete and near-complete responses in the first handful of recipients. Updated results will be presented at the 2022 meeting of the American Society of Clinical Oncology.

Table 1 Industry-sponsored γδ T cell–directed therapies in clinical trials

But TC BioPharm, like a handful of other firms, is focused first on deploying ‘naked’, unmodified cells — the goal being to harness the natural properties of γδ T cells to detect and destroy malignant cells while sparing normal, healthy tissues. In addition to OmnImmune — which is being trialed in a pre-transplant setting for patients with AML who did not respond well to first-line chemotherapy — there is INB-100, another unmodified γδ T cell candidate. INB-100 seems to help prevent relapse when used as post-transplant treatment for leukemia. Scientists at IN8bio, the company behind INB-100, reported phase 1 trial findings in March.

In parallel, several startups hope to modulate endogenous γδ T cells already present in patients’ bodies through the use of monoclonal antibodies (mAbs) and bispecific antibody drugs that activate or engage this particular immune cell population. Moreover, big pharmaceutical companies have begun investing in the space, as demonstrated by Takeda’s planned acquisitions of two γδ T cell firms — GammaDelta Therapeutics and Adaptate Biotherapeutics — and a January 2022 deal that saw Bristol Myers Squibb (BMS) partner with Century Therapeutics to develop a γδ T cell–based treatment for myeloma.

It’s not the first time the field has rallied around the idea of γδ T cell therapies. In the mid-2000s, several academic groups and at least one drug company, Innate Pharma, jumped on the γδ T cell bandwagon, although that early enthusiasm proved short-lived. In clinical trials, the cell therapies yielded underwhelming antitumor response rates, leading some to blame the poor quality and variable nature of the γδ T cells themselves, given that they were isolated and expanded from the patient’s own immune cells at the time. Innate’s Yannis Morel, head of product portfolio strategy and business development at the company, also notes how many fundamental aspects of γδ T cell biology were not known back then — for instance, it wasn’t until ten years ago that researchers in France first demonstrated the role that checkpoint proteins known as butyrophilins play in sensing cancer metabolites and regulating γδ T cell activation.

A lot has changed in the intervening years. And now, with a better understanding of γδ T cell recognition pathways and improved protocols for manufacturing large numbers of pure cells from healthy blood donations — or even from reprogrammed stem cells — the field is experiencing a resurgence in interest. “γδ T cells are the new black,” Bertaina quips. Opinions differ, however, on the best path forward.

One point of contention: is genetic engineering necessary to produce a viable therapy? According to TC BioPharm executive chairman Michael Leek, “CAR’ing may not be necessary” for certain blood cancers, such as AML, because infused γδ T cells will naturally traffic to the leukemic microenvironment in the bone marrow and exert their immune surveillance functions there. As such, he says of OmnImmune, “we can make large numbers of cells that are very efficacious without the need” for CAR modifications. And even in some solid tumors, CAR engineering may be superfluous, at least according to trial data from Zhinan Yin, an immunologist at Jinan University in Guangzhou, China, and the cofounder of JIDEI Kongming Biotech. His team treated a cohort of patients with late-stage lung and liver cancer with multiple infusions of unmodified γδ T cells. According to Yin, some who responded favorably to the therapy are still alive today, up to five years later.

But such dramatic responses are rare. What’s more, the cells don’t stick around for long — only a few months at most — unlike some engineered (and autologous) αβ T cell therapies, which can linger in circulation for a decade or more. That’s why Marta Barisa, a tumor immunologist at University College London who previously worked at TC BioPharm, thinks that ‘armored’ γδ T cells will ultimately win out. “You need some sort of engineering to overcome exhaustion, tumor suppression and rejection of allogeneic products,” Barisa says.

Bertaina similarly sees the long-term viability of the cells as “a major roadblock.” She may be involved in testing both modified products, as a scientific advisor to Adicet, and unmodified cell therapies, as a site investigator for a GammaDelta-sponsored trial. But in her mind, “we need to invest more in making these cells persist longer and stay activated longer,” she says.

In addition to Adicet’s CD20-targeted ADI-001, other CAR-engineered γδ T cells in or nearing clinical development include a therapy from Singapore’s CytoMed Therapeutics directed against natural killer group 2D ligand (NKG2DL); a programmed death ligand-1 (PD-L1)–targeted candidate from Kiromic BioPharma; and a CD7-directed product from Suzhou, China’s PersonGen BioTherapeutics. Gadeta has GDT-002, an autologous therapy in which patients’ own αβ T cells are engineered to express a defined γδ TCR. This creates an immune cell with the potent effector and helper functions of αβ T cells plus a broadly tumor-reactive high-affinity TCR that is decoupled from the regulatory constraints placed on γδ T cells. “It combines the best properties of both worlds,” says Gadeta co-founder Jürgen Kuball, a hematologist and tumor immunologist at the University Medical Centre Utrecht in the Netherlands. An academic trial testing the strategy has been ongoing for many years, and Gadeta launched its first study last year of GDT-002, for patients with multiple myeloma.

Then there is IN8bio, a University of Alabama at Birmingham spinoff formerly known as Incysus Therapeutics. In addition to its non-engineered product INB-100, the company has a transgene-modified therapy called INB-200 that entered clinical testing in 2020. For that therapy, the company transduces autologous γδ T cells with a lentivirus expressing methylguanine DNA methyltransferase (MGMT), an enzyme that confers resistance to temozolomide, an alkylating chemotherapy agent commonly used to treat high-grade gliomas. This allows the immune cells to function in the brain despite therapeutic concentrations of a drug that would otherwise deplete the therapeutic cell numbers.

For the moment, IN8bio is manufacturing its brain cancer treatment in bespoke batches on a patient-by-patient basis, a decision made two years ago to comply with regulatory constraints in place at the time. “Because we were the first in human with genetically modified γδ T cells,” says chief operating officer Kate Rochlin, the US Food and Drug Administration “wanted the safety of modified cells demonstrated first using an autologous approach.”

That safety was on display in a phase 1 clinical update presented at the American Society of Clinical Oncology meeting on 5 June. IN8bio next plans to begin trials with a donor-derived version of the therapy within the coming year. And in fact, practically every γδ T cell therapy entering the clinic today follows this allogeneic playbook. But looking further ahead, some competitors intend to derive their γδ T cells from induced pluripotent stem cells, the idea being to simplify the manufacturing and engineering processes while increasing consistency across product batches.

“It’s a homogeneous population that you can count on,” says Teri Foy, head of immuno-oncology research and early development at BMS, which is co-developing such a stem cell–derived cell therapy for myeloma with Century Therapeutics. Late last year, Century scientists described how they reprogram γδ T cells to yield pluripotent stem cells, edit those cells to express CARs, and then differentiate the cells back into antigen-specific, tumor-killing γδ T cells.

Besides debates over engineering requirements and starting cell sources, another dividing line in the field comes down to what kinds of γδ T cells companies hope to administer or activate for maximal therapeutic benefit. Many firms have built their therapies around the more abundant Vγ9Vδ2 (Vδ2+) subset, crafting selective expansion and differentiation protocols for isolating these types of γδ T cells, which are mainly present in peripheral blood. But others, including Takeda and Adicet, are focused on rarer Vδ1+ γδ T cells, a population of blood and tissue-resident cells that may better infiltrate tumors and help orchestrate localized anticancer responses.

“This [Vδ1+] subset has higher cytolytic activity,” says Christopher Arendt, head of Takeda’s global oncology development portfolio. “And then there’s the tissue-predilection part: these cells are wired to be there and to respond to homeostatic signals.”

Takeda’s interest in Vδ1+ γδ T cells takes two forms. Through its planned takeover of GammaDelta Therapeutics, the company is pursuing allogeneic cell therapies, starting with GDX012 for patients with AML. And through Adaptate, the company is developing Vδ1+-targeting antibody therapeutics, which may take the form of mAb agonists or bispecific engagers. Both companies trace their origins back to the laboratory of immunologist Adrian Hayday at King’s College London, with additional intellectual property provided by Bruno Silva-Santos and his colleagues at the University of Lisbon–affiliated Institute of Molecular Medicine.

“You could say these are different shots on goal,” Arendt says, “or you could say it’s a chance to go deep and really be a company that’s committed to understanding the value of [Vδ1+ γδ T cell] biology.”

Adaptate’s Vδ1+-targeted assets remain in preclinical development, but a few antibody therapies directed against Vγ9Vδ2 T cells are already in human testing. ImCheck Therapeutics, a company founded by cancer immunologist Daniel Olive at Aix Marseille University in France, has a butyrophilin 3A–targeted humanized Fc-silenced IgG1 mAb that activates Vγ9Vδ2 T cells. Phase 2 trials are ongoing to evaluate the drug, called ICT01, as a monotherapy for patients with ovarian cancer or head and neck squamous cell carcinoma, and in combination with a programmed death 1 inhibitor for patients with a range of solid tumors who failed prior checkpoint-blockade treatment.

On the bispecific front, Lava Therapeutics has two Vγ9Vδ2 T cell engagers in early clinical testing: one termed LAVA-1207 that is directed against prostate-specific membrane antigen, and a lead program, LAVA-051, that crosslinks the T cells to CD1d, a molecule found on a variety of tumors that also serves antigen-presenting functions for invariant natural killer T (iNKT) cells.

LAVA-051 serves double duty, explains CSO Hans van der Vliet, also a medical oncologist at Amsterdam UMC: it both brings the Vγ9Vδ2 cells to CD1d-expressing tumors and potentiates the interaction between CD1d and iNKT cells, “thereby uniquely activating two immune effector cell populations,” he says. Among the first few patients treated, the company could see biomarkers consistent with that mechanism at work — “a potential sign of immunological activity,” van der Vliet says.

One more outside-the-box antibody strategy comes from PureTech Health. In collaboration with researchers at New York University Langone Health, the company is developing a fully human IgG1 mAb called LYT-210 that targets and destroys γδ T cells bearing Vδ1+ receptors.

These cells, when activated and polarized with the right cytokine stimuli, exert robust antitumor effects. This explains why Takeda (via GammaDelta) and Adicet are administering those types of γδ T cells, derived from healthy donors, in their trials. But Vδ1+ γδ T cells “are not set in stone,” notes Aleksandra Filipovic, head of oncology at PureTech Health. In the tumor microenvironment, the same cell population can become immunosuppressive, meaning they can be both friends and foes to cancer, depending on the circumstances.

Thus, although it may seem counterintuitive that some companies are building adoptive therapies around Vδ1+ γδ T cells, whereas PureTech has a preclinical-stage asset designed to deplete the same cell subtype, Filipovic sees no conflict between the strategies. “The two approaches do not contradict each other,” she says. “They’re actually complementary.” And as some researchers have suggested, one could even imagine combining the approaches, using a mAb like LYT-210 to deplete the protumor γδ T cell subgroup in a patient before going back to administer a replacement set of γδ T cells with strong antitumor functions.

The bottom line, says Filipovic: “We cannot forget the context into which we’re delivering these cells.”

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Dolgin, E. Unconventional γδ T cells ‘the new black’ in cancer therapy. Nat Biotechnol 40, 805–808 (2022). https://doi.org/10.1038/s41587-022-01363-6

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