Gamma Delta T Cells Unlock New Advances in Cancer Immunotherapy

γδ T cells have emerged as a compelling avenue of research and therapeutic exploration in oncology. While much attention has been given to CAR T-cell therapies historically, γδ T cells offer a promising approach, especially in combating challenging malignancies, explained Lawrence Lamb, PhD, executive vice president, chief scientific officer, and co-founder of IN8bio, during a session at Precision Medicine World Conference (PMWC) 2025 in Santa Clara, California.

γδ T cells differ significantly from classical αβ T cells, according to Lamb. Unlike αβ T cells, which rely primarily on their T-cell receptor to recognize antigens presented on major histocompatibility complex molecules, γδ T cells also express NKG2D, a receptor that enables them to recognize stress-induced ligands on target cells. This dual recognition mechanism positions γδ T cells as key players in the early immune response to cancer. They are often the first responders to stressed or pre-malignant cells, taking on a pivotal role before tumors have fully developed.

“We develop stressed or pre-malignant cells every day, and our innate immune system takes care of them for us, so we never usually feel that occur. When we get a tumor population start to grow, then you start getting clonal mutation and then subclonal mutations, and what happens is you get a rapid neoantigen generation and a tumor microenvironment, and the adaptive immune system is trying to keep up, but they just can't—the tumor is growing too fast. Same with your innate immune system, such as γδ T cells, they are consumed in the fight. They're almost gone in a patient that presents with a new leukemia,” Lamb said during the PMWC session.

3D rendering of leukemia cells floating in the bloodstream. Image Credit: © Nicat - stock.adobe.com

For instance, in pediatric patients newly diagnosed with acute leukemia, Lamb noted that his lab has observed a disappearance of circulating γδ T cells, underscoring their significant role in early tumor response and their potential for therapeutic application. However, for γδ T cells to achieve optimal therapeutic efficacy, specific conditions must be met. First, therapy should target a small or undetectable tumor burden, where the ratio of immune cells to cancer cells is most favorable. Second, intervention should occur early in the disease process, before tumors have had the opportunity to mutate extensively or develop an immunosuppressive microenvironment. Finally, sustained therapeutic pressure on the tumor is critical for long-term success.

A groundbreaking approach to harnessing γδ T cells emerged from early observations in haploidentical (haplo) transplants, according to Lamb.

“Back in 1992 when I was post-doc, we were doing haplo transplant with αβ T cell depletion. We gave a graft to the patient from a haplo donor who had been depleted of αβ T cells. At about a year or so in, we began to see patients running high numbers of γδ T cells,” Lamb said. “I thought, Geez, this is interesting. About a quarter of our patients have increased γδ T cells. Let's see what else they're doing. To my surprise, [these patients] were all alive. In a year, most of the others were dead. These were patients who had been given multiple lines of therapy and were only referred to us because it was their last chance before giving up.”

For Lamb, this discovery prompted further investigation into the biology of γδ T cells, revealing their potent ability to target leukemia cells while sparing healthy cells.

“We did some biology, and we showed the γδ T cells could kill leukemia, and that they didn't kill normal cells or kill third-party normal cells,” Lamb said. “After many years of watching the technology improve to where we could actually manufacture cells, we developed a clinical trial where we again [conducted] haplo transplant.”

Taking an apheresis product from the haplo donor, Lamb manufactured the γδ T cell graft and froze it for later use. Patients underwent conditioning regimens, including chemotherapy and total body irradiation, followed by infusion of the γδ T cell graft post-transplant and post-transplant cyclophosphamide as graft-versus-host disease prophylaxis, which also furthers lymphodepletion, according to Lamb.

“Within 10 days of neutrophil engraftment, we deliver the γδ T cell graft, and then we watched the patient to see how well they reconstitute,” Lamb said. “We have 100% survival in our patients with acute myeloid leukemia [AML]. We have 2 patients with TP53 mutations with acute lymphoblastic leukemia that have relapsed and died slightly beyond a year. So right now, it's looking pretty good for AML. We continue to accrue on this trial and in an expansion cohort, and we will be updating this at the ASTCT meeting in Honolulu, and then probably again at ASH later this year.”

Unlike CAR T cell therapies, where concerns about cell persistence and durability often arise, γδ T cells offer the advantage of long-term reconstitution. This sustained presence appears to provide ongoing protection, making them an attractive option for durable cancer control.

Photomicrograph showing the histology of glioblastoma multiforme. Image Credit: © DMH - stock.adobe.com

Notably, Lamb explained that the potential therapeutic applications for γδ T cells is not limited to hematologic cancers. γδ T cells are also being explored in solid tumors, including glioblastoma, which is a particularly aggressive and challenging brain tumor. However, the approach to solid tumors often differs from hematologic malignancies due to the unique tumor microenvironments and physical barriers involved. For example, in glioblastoma, tumor removal by surgery is often the first step. However, residual disease and scattered tumor cells remain a significant challenge. In such cases, γδ T cells can play a critical role.

“With a very large [glioblastoma] tumor, there is no CAR T in the universe that is going to wipe it out,” Lamb said. “But you don't have to worry about that, really, because your surgeon is going to take that out. What you do have to worry about is all the little things on the periphery, the little pockets of cells here and there that haven't yet developed a microenvironment and haven't yet organized into a tumor mass.”

Lamb explained that he addressed this residual disease by layering the therapy on top of the step regimen. By doing this, he found that it was possible to increase NKG2D ligands to very high levels on glioblastomas at around 8 hours after chemotherapy, and then they would decrease.

“We were faced with having to do the chemotherapy and the cell therapy at the same time, which was kind of impossible, because the chemotherapy would kill the cells. So, we co-opted the MGMT gene that protects the brain tumor, and we put it in the γδ T cell, and the γδ T cell survives and functions in a chemotherapy rich environment quite well. So, during the standard of care, we insert a catheter in the brain tumor cavity after the surgeon removes the tumor. This is a Rickham reservoir. Then we do apheresis,” Lamb said.

In an allogeneic setting, the patient then gets consolidation therapy with temozolomide (Temodar; Merck & Co) and radiation, and then 6 cycles of temozolomide as maintenance, Lamb explained.

“With the first cycle of each 28 days, we deliver the temozolomide intravenously to control bioavailability. Within 4 hours of that, we put a 1x10⁷ gene-modified activated γδ T cells in their head. We carry this on for 6 cycles,” Lamb said. “The rationale is because the brain tumor doubles at about 65 days or so, we give the therapy in 28 days, and we're hoping to cut this tumor off from the knees every time it tries to get back up.”

Early results from this study are encouraging, according to Lamb. Patients in the second dose cohort include one MGMT-unmethylated individual who remains progression free at 4 years post-treatment, and another patient nearing 29 months of survival. Most patients receiving 6 doses have surpassed 1 year of survival, with several continuing to do well.

“We've had a few relapses and deaths, but we expect that with glioblastoma,” Lamb said. “Overall, I think that this is very encouraging. But even more so, the patients that have relapsed, we've been able to take their tumor out and have a look at it. What we're able to see is immune activation within the tumor. In the biopsy, you see γδ T cells infiltrating the tumor quite well at 150 days after the injections were done. They're also drawing in CD3 and CD8 cells, bringing in an adaptive response as well that were not present in the primary tumor.”

REFERENCE

Lamb L. Advances in allogeneic cell therapies: overcoming hurdles and expanding applications. Precision Medicine World Conference; February 5-7, 2025; Santa Clara, California.