Therapeutic Immune Manipulation

Chimeric antigen receptor (CAR) T-cell therapy was a major breakthrough in immunotherapy. To date, according to the Alliance for Cancer Gene Therapy, seven therapies have been approved for blood cancers such as Kymriah^® and Yescarta^®. As extraordinary as these CAR T-cell therapies are, the approach struggles with solid tumors, as well as adverse side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) resulting from in vivo T cell expansion. Complex manufacturing for autologous therapies and resultant costs limit the number of patients that can be treated.

Alternative approaches to engaging the immune system have been explored for decades, for instance, bispecific T-cell engager (BiTE) technology pioneered by Amgen. Companies like Artiva Biotherapeutics and Dragonfly Therapeutics are exploring the benefits that natural killer (NK) cells can bring, especially in B cell driven autoimmune diseases. Additionally, rare T cell populations such as invariant natural killer T (iNKT) cells are being harnessed to perform beyond their normal capabilities. Scientists also continue to innovate to try and bring solid cancers with edgy antigens under clinical control.

Importantly, autologous CAR T-cell therapy illustrated that the immune system can be exploited to combat disease as well as the challenges that need to be addressed when doing so. The next generation of immunotherapies is beginning to progress through clinical trials, and a new class of drugs could potentially be introduced for autoimmune diseases as well as oncology indications.

Harnessing the immune system

“BiTE^® technology was developed to address an important unmet need in cancer care,” said Jean-Charles Soria, MD, PhD, senior vice president, global oncology development at Amgen. “For 30 years, we have built on this science, first in blood cancers and more recently in solid tumors.”

While the immune system has a natural ability to recognize and kill cancer cells, tumors can develop ways to evade that response. BiTE therapies bring T cells into direct contact with tumor cells by binding both CD3 on the T cell and a specific antigen on the tumor cell, activating T-cell-mediated killing.

BiTE and CAR T-cell therapies are distinct, complementary approaches that harness the immune system to fight cancer, according to Soria. BiTE “off-the-shelf” therapies are designed to redirect a patient’s own T cells to recognize and eliminate tumor cells expressing a selected target. This can enable treatment without the individualized cell collection and manufacturing process required for CAR T therapy.

Both platforms have demonstrated meaningful clinical benefits in appropriate settings. The optimal approach depends on the disease, the target biology, the patient’s condition, practical treatment considerations, and the totality of clinical evidence. “BiTE therapies may be particularly well suited to cancers with targets that are frequently and consistently expressed on tumor cells, with limited expression in healthy tissues,” said Soria.

Amgen continues to explore the impact of existing BiTE therapies, including the potential to address needs earlier in the small cell lung cancer treatment journey, and the potential to combine BiTE therapies with other innovative mechanisms of action. “We are also investigating new assets across additional tumor types. This includes xaluritamig, an investigational STEAP1-targeted BiTE in advanced clinical development for prostate cancer, where immunotherapy has historically had limited success,” Soria elaborated.

As the understanding of cancer biology grows, immunotherapy will become increasingly precise. Amgen’s focus is to translate deep insights in human genetics and disease biology into the right targets and therapeutic approaches to provide meaningful new options. The company brought to market the first globally approved BiTE molecule in hematologic malignancies, and the first FDA-approved BiTE therapy for a common solid tumor, small cell lung cancer.

Bumping up defenses

“The role of any cell therapy is to very potently kill the pathogenic B cells. We use non-genetically modified NK cells in combination with monoclonal antibodies (mAbs) such as Rituxan^® for targeting the antigen on the B cell,” said Fred Aslan, MD, CEO at Artiva Biotherapeutics.

The Fab region of the mAb binds to the antigen on the B cell while the Fc portion binds to CD16 on the NK cell surface. This three-way binding activates the NK cell to kill the B cell. Given alone, Rituxan relies on endogenous NK cells that can be lowered or have low activity in patients with B cell cancers or autoimmune diseases. Dosing billions of NK cells simultaneously with the mAb positions the mAb to do more.

Importantly, since NK cells do not expand in vivo, serious side effects that result from T-cell expansion, CRS and ICANS, are avoided allowing therapeutic infusions outside of large hospital settings. However, the high dosages necessitate a robust manufacturing process.

A spin-off of Korea-based GC Cell, Artiva Biotherapeutics’ largest differentiation is its scalable process to manufacture NK cells. Umbilical cord units are selected from individuals with high affinity CD16 on the NK cells. Each umbilical cord creates about 50 intermediates that, in turn, each produce about 80 billion cells. “At a dose of eight billion cells, we can treat about 500 patients with a single umbilical unit. The COGS is a magnitude less than autologous CAR T-cell therapy,” said Aslan.

The company tested the NK cells with multiple targeting mAbs in two oncology and five autoimmune indications, close to 150 patients to date, to generate comparison data between the mAb and the combination therapy.

For example, using Rituxan alone, the average patient had an incomplete depletion; one B cell/ mL remained in the blood. In the combination therapy, no B cells were evident across all indications. In studies with aggressive non-Hodgkin lymphoma and Hodgkin lymphoma using a CD40 antibody, the complete response rate and durability were in line with autologous CAR T-cell therapy. Initial results with autoimmune disease also demonstrated results in line with autologous CAR T-cell therapy.

Artiva Biotherapeutics’ lead indication is refractory rheumatoid arthritis. They are initiating a Phase III trial with data expected by 2028.

Matching depletion to disease

The platform approach of Dragonfly Therapeutics for autoimmune disease spans CCR6, CD19, BAFFR, FAP, CD52 and BCMA, each aimed at a different pathogenic population and a different set of diseases, from lupus nephritis to fibrosis to amyloidosis.

The novel immune engagers include both first-in-class mAbs and trispecific immune cell engagers (TriNKETs). TriNKETs are antibody-like molecules with three binding arms: one for an antigen, one for NKG2D, and one for CD16. Both NKG2D and CD16 are activating receptors on NK cells.

In autoimmune disease, CAR T cells and Dragonfly Therapeutics’ biologically native immune engagers both aim for deep depletion of pathogenic B cells and an immune reset, but employ different routes. Not only do NK cells not require the same massive clonal expansion as T cells, but, additionally, NKG2D activation is already tuned by the body to respond to stressed cells. These facets can give a wider window between a depleting versus a harmful dose, sidestepping CAR T toxicity emerging in autoimmune disease.

Recruiting the patient’s existing cells means no expansion phase, no lymphodepletion, no gene modification of a living cell, and, therefore, no secondary malignancy risk from the product itself. A half-life measured in days makes the effect dose-controllable and reversible.

The company’s most clinically advanced autoimmune program, DF5112, a CCR6-targeting mAb, offers a multimodal approach. Overall, DF5112 is designed to deplete pathogenic CCR6+ cells and inhibit chemotaxis, minimizing tissue inflammation, providing benefit across several autoimmune diseases, including psoriatic arthritis, rheumatoid arthritis, lupus, hidradenitis suppurativa, and others.

Near completion of Phase I, the DF5112 CCR6 mAb sits on the specific cells that drive tissue inflammation in many autoimmune diseases, Th17 cells and a subset of memory B cells, while sparing the bulk of the immune system. It is the first molecule to deplete both at once. Early data are on track to be shared end of 2026.

According to Dragonfly Therapeutics, the next generation of immunotherapy is about depleting exactly the right cells. As different autoimmune diseases are driven by different cells, the company is building a toolkit that can match the depleted cell to the disease biology.

Utilizing distinct T cells

Another approach is utilizing iNKT cells. iNKT cells are a distinct T cell population with an internal targeting and homing device (iTCR) and modulate both arms of immunity, innate and adaptive. They naturally hone to tissues, promote tumor killing, viral clearance, suppress inflammatory cytokines and GvHD.

MiNK Therapeutics believes that due to iNKT cell biology these cells may represent a foundational approach to immune restoration applicable across a broad range of conditions. iNKTs have shown benefit in treating solid tumor cancers in their native form and MiNK Therapeutics has demonstrated that these cells can be engineered or edited for super-targeting. Clinical data show no neurotoxicity or CRS at 1 billion cells/ dose.

The company’s lead program, agenT-797, an allogeneic, off-the-shelf iNKT-cell therapy, is being evaluated in virally induced acute respiratory distress syndrome (ARDS), where a favorable safety profile, increased survival rate, and decreased secondary infection rates have been observed.

Reprogramming tumors

CAR T cells struggle with solid tumors. Almost no antigens are found solely on tumor cells, plus the antigens that exist are patchy, and get lost over time. According to a USC research team one fix is to install an antigen, but only if the installation stays inside the tumor.¹ The concept is turning a signal the tumor controls into one the physician controls in a safe manner.

Tumor hallmarks like hypoxia are a reasonable biological address, but not a safe one to use alone since brain, liver, bone marrow and gut are also low in oxygen. Focused ultrasound (FUS) gives a precise physical address, but heat-shock-driven expression is a brief spike that fades before T cells can do much.

Therefore, the research team combined inputs to develop SHIFTERS (solid-tumor hallmark inducible, focused-ultrasound triggered enhanced reprogramming system), a two-key AND gated circuit that rewires tumor hallmarks into the clinically-validated antigen CD19 under FUS control. Hypoxia turns on one half of a split Gal4-VP64 transcription factor; FUS heating turns on the other half. Both need to be present for the halves to assemble and switch on CD19.

To test the hypothesis, the circuit was pre-installed in tumor cell lines then CD19 synNotch/estimated glomerular filtration rate (EGFR) CAR T cells were infused into 3D spheroids and in vivo immunodeficient mice models. The cells get “primed” by the induced CD19, and then kill surrounding tumor cells via EGFR. Killing stays localized; priming wears off quickly once T cells leave the area.

Testing across different oxygen levels showed the switch only fired at tumor-like one percent, ignoring normal low-oxygen tissue. SHIFTERS holds 60-80% expression through 72 hours, then returns to baseline by about day six; durable enough to work, reversible enough to be safe. With only 25% of tumor cells induced, more than half the entire population was killed.

SHIFTERS is modular. Swapping hypoxia for a liver-cancer-specific promoter reproduced the process in liver cancer cells only, with near-zero activity in other cell types. Next steps include adding ultrasound-gated cytokines (IL-2, IL-18, interferon-γ) to counter tumor immunosuppression without systemic toxicity; building a library of other tumor-hallmark promoters for other cancers; and working out the right FUS dosing schedule and behavior in immunocompetent models.

References

1. Guo T, Zhu Z, Qu Y et al. Ultrasound priming gated by solid tumor hallmarks to guide CAR-T therapy. Sci Adv. 2026 Jun 12;12(24):eaed0666. doi: 10.1126/sciadv.aed0666.

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