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CAR T cell therapies have revolutionized outcomes for certain blood cancers, yet their impact on solid tumors has lagged. The field has long wrestled with T cell exhaustion—a state in which engineered cells lose their potency and fail to sustain an anti‑tumor response.

At this year’s AACR annual meeting in San Diego, researchers from the Perelman School of Medicine at the University of Pennsylvania presented first‑in‑human Phase I data pointing to a possible solution. Their novel “KIR‑CAR” T cell therapy demonstrated a favorable safety profile and early signals of activity across multiple solid tumor types.

The investigational therapy, SynKIR-110, represents a departure from traditional CAR T designs. Rather than using a single-chain receptor, the therapy is modeled after natural killer (NK) cell receptors and uses a “multi-chain” architecture.

This design separates tumor recognition from activation, effectively creating an intrinsic “on-off” mechanism. The T cell remains in a resting state until it encounters its target, at which point the receptor components assemble to trigger an immune attack.

“The KIR-CAR design provides a natural ‘on-off’ mechanism, which helps avoid the problem of T cell exhaustion,” said Janos L. Tanyi, MD, PhD, principal investigator of the study. “The CAR turns on when it finds its target, kills it, and then rests, rather than constantly burning energy.”

This contrasts with conventional CAR T cells, which remain continuously active and can become depleted over time, limiting their effectiveness—particularly in the more complex microenvironment of solid tumors.

The Phase I dose-escalation trial enrolled nine patients with advanced, mesothelin-expressing cancers, including ovarian cancer, mesothelioma, and cholangiocarcinoma. These patients had limited treatment options, having received an average of four prior lines of therapy.

Although the primary goal of the study was to assess safety, early signs of efficacy were observed. Disease stabilization was reported in four patients, and one patient in the highest dose cohort achieved an ongoing partial response.

“These are cancer types that have never had an approved cell therapy,” Tanyi said. “We’re seeing good efficacy signals, even at low doses, and limited toxicity.”

The results suggest that the therapy may be able to generate meaningful anti-tumor responses even in heavily pretreated populations.

Safety has been another major barrier for CAR T therapies, particularly in solid tumors. However, the KIR-CAR approach appears to mitigate some of these concerns.

No dose-limiting toxicities were observed in the initial cohorts. Cytokine release syndrome (CRS), a common side effect of CAR T therapy, occurred in 33% of patients but was limited to low-grade events. Notably, there were no cases of immune effector cell-associated neurotoxicity syndrome (ICANS), a more severe complication sometimes seen with CAR T therapies.

The ability to limit toxicity while maintaining activity is a key step toward broader application of cell therapies in solid tumors.

SynKIR-110 targets mesothelin, a protein expressed on the surface of several solid tumors but largely absent from normal tissues. This makes it an attractive target for immunotherapy, particularly in cancers such as ovarian cancer and mesothelioma, where treatment options are limited.

The trial results indicate that the therapy’s activity is not confined to a single tumor type, raising the possibility of broader applicability across mesothelin-expressing cancers.

The findings come amid growing efforts to adapt CAR T technology for solid tumors. While the approach has revolutionized hematologic malignancies, solid tumors present additional challenges, including immunosuppressive microenvironments, physical barriers to T cell infiltration, and antigen heterogeneity.

Researchers are exploring multiple strategies to address these barriers, including improved targeting, combination therapies, and next-generation receptor designs such as KIR-CAR.

As noted by CAR T pioneer Carl June, MD, advancing cellular therapies into solid tumors remains a central goal for the field.

The Phase I study continues to enroll patients, aiming for a 42‑person cohort to define the maximum tolerated dose ahead of Phase II. Early readouts show that CAR T expansion rises with dose, a pattern that may translate into stronger anti‑tumor activity at higher levels.

While still preliminary, the findings highlight the potential of multi‑chain CAR designs to sustain activity without added toxicity. If confirmed, KIR‑CAR therapies could usher in a new generation of engineered immune cells that more closely mirror natural immune regulation.

For now, the data offer a promising sign that CAR T innovation may finally be gaining ground in solid tumors.

The post Novel KIR‑CAR T Approach Shows Early Activity Against Solid Tumors appeared first on GEN – Genetic Engineering and Biotechnology News.

Researchers at Memorial Sloan Kettering (MSK) Cancer Center have identified the earliest cellular and molecular events that create the needed conditions for lung cancer cells to begin their growth into a tumor. The study, published in Nature, describes how cells with cancer-causing mutations initiate a coordinated chain of events to involve nearby fibroblasts and immune cells to create a microenvironment conducive to tumor growth at the very start of disease.

“We also found that this transformation of the local neighborhood is reversible, if caught early enough. This opens the door to new treatment and prevention strategies,” said senior author Joo-Hyeon Lee, PhD, an associate member in the developmental biology program at MSK.

The research focused on lung alveolar type II (AT2) stem cells that acquire mutations in the KRAS gene. Rather than simply proliferating, the mutant cells enter a regenerative-like state that resembles tissue repair. In this state, they produce amphiregulin (AREG), a signaling molecule that initiates communication with surrounding cells. AREG activates nearby fibroblasts through EGFR signaling, which prompts them to adopt a fibrotic, injury-like state which results in a remodeling of the extracellular matrix.

Within the microenvironment created, fibroblasts play a central role in shielding emerging tumor cells by producing a fibrous scaffold that supports tumor growth while also releasing signals that alter the activity of immune cells. Macrophages recruited to the site undergo reprogramming, shifting away from fighting the tumor toward phenotypes that suppress immune responses. Neutrophils and regulatory T cells are also recruited, further dampening anti-tumor immunity. This coordinated activity creates a protective niche in which the cells with the KRAS mutation can grow without being eliminated.

“These reciprocal interactions establish a self-sustaining epithelial–stromal–immune circuit that generates a tumor-permissive niche before malignant outgrowth,” the researches wrote. This loop reinforces itself: mutant cells sustain fibroblast activation, fibroblasts reshape immune responses, and immune cells further support tumor-promoting conditions.

The study builds on prior research in the Lee lab into lung injury and repair, which showed that normal regenerative programs involve temporary activation of stem cells and fibroblasts. In cancer, however, this process becomes dysregulated. Mutant cells remain locked in a regenerative state, continuously signaling to their environment. Earlier work by the same group had identified these regenerative states as a feature of early tumorigenesis.

To identify the mechanisms involved, the MSK first used mouse models of lung cancer carrying KRAS mutations. Through lineage tracing and single-cell analyses, they tracked individual cells to map how interactions with fibroblasts and immune cells evolved over time. They then used tissue samples from patients with early-stage lung adenocarcinoma and found returned the same result of cancer cells producing high levels of AREG and adjacent fibrotic fibroblasts.

Importantly, the team demonstrated that disrupting this communication network can prevent tumor formation. Blocking AREG signaling with an EGFR inhibitor kept fibroblasts and immune cells in their normal states and significantly impaired tumor development. Similarly, removing the AREG gene from mutant cells prevented the formation of the tumor-supportive niche. Even after early lesions had formed, inhibiting KRAS activity reversed many of the changes that had already occurred in the microenvironment.

The implications of this research to influence for cancer care are substantial. The identification of early signaling events and microenvironmental changes suggests new biomarkers for detecting lung cancer before it becomes advanced. High levels of AREG or evidence of fibroblast activation could indicate the presence of precancerous lesions, which could be particularly important for screening those at high risk of developing cancer, such as long-term smokers.

The findings also suggest there could be the development of new therapeutics aimed at preventing cancer development as opposed to treating it once it is established. By targeting the AREG–EGFR signaling axis or disrupting fibroblast activation, clinicians may be able to block tumor development at its earliest stages. Because the team showed these processes can be reversed, there is a window for intervention before the disease becomes resistant to treatment.

“The reversibility of these preneoplastic circuits defines a therapeutic window before progression to treatment-resistant disease,” the researchers wrote.

Next steps for the team include validating biomarkers in clinical populations, refining organoid models to study patient-specific tumor development, and testing preventive therapies that target these newly identified early signaling pathways.

The post Earliest Events of Lung Cancer Development Mapped appeared first on Inside Precision Medicine.