Foreigners are travelling to China for low cost CAR T cancer therapy

Good news! Competition is good, more competition is better!

"China is becoming a destination-of-choice for foreign nationals with cancer looking for cheaper, faster CAR-T-cell therapy. Michael Walters, a 25-year-old from New Zealand with blood cancer, travelled to SinoUnited Hospital in Shanghai to receive CAR-T-cell therapy at less than half the cost of what he would have paid in Australia or the United States. He is now in remission. “China has basically done to CAR-T-cell therapy the same thing that it’s done to other industries, which is, they’ve industrialized it,” ..."

Nature Briefing: Cancer

Patients Are Flying to China for the Latest Cancer Treatment (behind paywall) "Shanghai is a favored destination, with lower costs than the West and innovation in biotechnology"

New mRNA immunotherapy eliminates pancreatic tumors in mice

Good news! Cancer is history (soon)!

"... have developed an immunotherapy using a cocktail of messenger RNAs (mRNA) that could potentially transform pancreatic cancer treatment.

The study ... combines immune cytokine and tumor-associated antigen mRNAs into a single injection to treat pancreatic ductal adenocarcinoma.

Approximately 50% of mice with pancreatic cancer treated with the mRNA immunotherapeutic cocktail had complete tumor responses and, more impressively, remained disease-free for a year, even after treatment had stopped. 

"It's unheard of to get a response like this in these models of pancreatic cancer," ..."

From the abstract:

"Immunotherapy has limited success in pancreatic ductal adenocarcinoma (PDAC) due to an immune exclusive tumor microenvironment (TME) that lacks many cytokines necessary for Natural Killer (NK) and T cell responses.

Here, we design multiplexed mRNAs encoding interleukins, chemokines, and interferons as a safe and effective cytokine therapy for PDAC.

Intratumoral injection of IL-12, IL-18, CCL5, CXCL10, and IFNβ mRNAs achieves robust yet transient cytokine expression, leading to NK and CD8+ T cell activation and reduced tumor growth and fibrosis in PDAC transplant mouse models.

Combining cytokine with tumor antigen mRNAs enhances dendritic cell antigen presentation and CD8+ T cell priming locally and systemically that prolongs animal survival after a single dose.

Remarkably, nanoparticle encapsulation of the cytokine/antigen mRNA cocktail allows systemic administration and local delivery to autochthonous PDAC tumors in mice, culminating in curative responses in 50% of animals and antigen-reactive T cell persistence.

These results suggest that multiplexed mRNA approaches to deliver cytokines and antigens generally absent in the TME could pave the way for effective immunotherapy in PDAC."

New mRNA immunotherapy eliminates pancreatic tumors in mice

mRNA immunotherapy developed by UMass Chan scientists eliminates pancreatic tumors in mice (original news release)

Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer (open access)

Fig. 2: A multiplexed cytokine mRNA cocktail mobilizes innate and adaptive immunity and reduces tumor growth and desmoplasia in “cold” PDAC-bearing mice.

Fig. 3: Combinatorial cytokine mRNA therapy can achieve robust cytotoxic T cell immunity in a “hot” PDAC model after a single dose.

Cell therapy substantially reduces severe rheumatoid arthritis in first clinical trial

Good news, but a very small sample size! Impressive!

"Immunotherapies such as CAR T-cell therapy are used primarily to treat cancer. In the future, these patient-specific therapies, manufactured from patients’ own immune cells, could also help cure autoimmune diseases.

Six patients with particularly severe rheumatoid arthritis have now received this treatment at Charité – Universitätsmedizin Berlin. In the journal Nature Medicine*, the researchers report the results from the world’s first clinical trial of its kind: Disease activity decreased substantially in all participants. By the end of the observation period, three of the patients no longer required any medication for rheumatoid arthritis. ...

Currently available treatments can usually keep the inflammation under control, but do not cure the disease. Patients therefore require lifelong medication ...

For the world’s first clinical trial to evaluate the safety and efficacy of a CD19 CAR T-cell therapy in rheumatoid arthritis, the research team ... initially enrolled six patients with particularly severe disease. The three women and three men, aged 31 to 69, had received up to eight targeted or biologic therapies over the previous ten years, none of which had been sufficiently effective. ...

For the researchers, the results from the first part of the COMPARE trial are highly encouraging: “Disease activity decreased markedly in all six patients. During follow-up of up to one year, three patients were in sustained remission without any medication for rheumatoid arthritis,” ..."

From the abstract:

"Chimeric antigen receptor (CAR) T cell-mediated B cell depletion has demonstrated efficacy in several autoimmune diseases.

Here we report clinical and molecular data obtained during the nonrandomized phase 1 part of the phase 1/2 COMPARE trial, evaluating safety and efficacy of mivocabtagene autoleucel (miv-cel), an autologous fully human CD19 CAR T cell therapy, in rheumatoid arthritis (RA).

Six patients (three men, three women) with severe, treatment-refractory, anti-citrullinated protein antibody (ACPA)-positive RA received a single infusion of miv-cel after stopping all disease-modifying antirheumatic drug treatments and after standard lymphodepletion therapy.

Patients were followed for 36–52 weeks for safety and efficacy.

Primary endpoints were the incidence and severity of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and adverse events (AEs) within the first 4 weeks after treatment.

Secondary and explorative endpoints assessed clinical efficacy and cellular and humoral immune responses.

CRS occurred in all patients and was limited to grade 1 and 2 events. No ICANSs or serious AEs occurred; one dose-limiting toxicity was recorded (grade 3 transaminase elevation, resolved without sequelae).

The primary endpoint was met with acceptable safety findings, allowing advancement to phase 2.

CAR T cell therapy resulted in depletion of CD19+ B cells across blood and tissue, coinciding with a continuous decline of autoantibodies with seroconversion in four of the six patients for ACPAs against mutated citrullinated vimentin and five of six for rheumatoid factor immunoglobulin M.

Despite cessation of immunosuppressive treatments, disease activity improved in all patients (median 34% DAS28-CRP reduction at the latest follow-up with DAS28-CRP remission and American College of Rheumatology 70% response in 3 of 6 patients).

CD19 CAR T cells showed acceptable short-term tolerability in patients with treatment-refractory RA, justifying further evaluation. ..."

Cell therapy substantially reduces severe rheumatoid arthritis in first clinical trial

Charité study demonstrates efficacy of CD19 CAR T cells in first patients  (original news release)

CD19 CAR T cell therapy for treatment-refractory seropositive rheumatoid arthritis: a phase 1 trial (no public access)

Patients own immune cells genetically modified in the laboratory, track down the disease driving B cells, even deep within tissues. Inflammatory foci such as those seen here around the knee joints of a study participant (magenta) are no longer detectable even several months after CD19-CAR T-cell therapy (right in the PET-MRI image). Swelling and pain have subsided, with improved mobility.

Individualized mRNA vaccine combination treatment Triumphs Over Melanoma

Good news! Cancer is history (soon)!

"An mRNA vaccine to treat the deadliest form of skin cancer has met a major milestone on the path to a new treatment, according to clinical trial results released today by Merck and Moderna.

If approved by the FDA, it would become the first ever mRNA-based cancer treatment and pave the way for similar treatments for other cancers—representing “the next frontier of cancer immunotherapy,” ...

Phase 3 clinical trial results showed that the experimental drug—intismeran autogene—prevented recurrence and metastasis of removed melanoma tumors when combined with the immunotherapy Keytruda. The companies have not released the full phase 3 results, but earlier phase 2 trials reported that risk of recurrence or death was reduced by nearly half after five years. ..."

"First and only combination regimen to demonstrate statistically significant and clinically meaningful improvements in RFS and DMFS compared to KEYTRUDA alone for these patients in the adjuvant melanoma setting

The Companies plan to present data at an upcoming international medical meeting and will engage with regulators on filing submissions for intismeran autogene in combination with KEYTRUDA

Intismeran autogene is an mRNA-based individualized neoantigen therapy (INT) designed specifically for each patient based on the unique set of mutations within their tumor to train and activate the immune system to recognize and fight cancer

...

The trial met its primary endpoint of recurrence-free survival (RFS) and a key secondary endpoint of distant metastasis-free survival (DMFS). This represents the first positive Phase 3 readout for an individualized neoantigen therapy (INT) and for an mRNA-based cancer therapy, as well as the first Phase 3 study to demonstrate a clinically meaningful improvement over KEYTRUDA alone, a standard-of-care immunotherapy, in the adjuvant setting for patients with resected melanoma. ..."

Global Health NOW: In the ‘Next Frontier’ in Cancer Treatment, mRNA Triumphs Over Melanoma’; and All Eyes on Australia as Social Media Ban Plays Out

Merck and Moderna Announce Phase 3 INTerpath-001 Trial of Intismeran Autogene Plus KEYTRUDA® Met Endpoints of Recurrence-Free Survival (RFS) and Distant Metastasis-Free Survival (DMFS) in Patients With Completely Resected Stage IIB-IV Melanoma (original news release)

Cell therapy successfully treats terminal, incurable, and deadly brain cancer in children

Good news! Cancer is history (soon)!

"An experimental immunotherapy has staved off brain tumours that would usually be incurable in four children. The therapy trains immune cells in a person’s blood to target three protein markers found in paediatric brain cancers.

The tumour-associated antigen T-cell therapy was given to 33 children and young adults with brain tumours that are usually fatal.

One patient with DIPG, a type of cancer that is usually fatal within a year, is alive two years post therapy.

Three others with other types of aggressive or recurrent brain cancers remain disease-free between two and five years on.

It is unclear why the treatment worked in some and not others. The small safety trial doesn’t deliver a cure yet, but the therapy doesn’t require genetic engineering, can target multiple proteins and might work better for solid tumours than chimeric antigen receptor (CAR)-T-cell therapy."

"Key takeaways:

• The multi-target design may help address tumor heterogeneity, one of the major barriers to successful treatment of aggressive childhood cancers.
• The trial successfully established a feasible manufacturing process, identified a maximum tolerated dose and defined an early safety profile – key milestones needed to advance the therapy into future Phase 2 studies.
• Researchers analyzed patients with DIPG or relapsed brain cancers, showing both responses and prolonged disease control, with some patients remaining disease-free years after treatment.

..."

From the abstract:

"Central nervous system (CNS) tumors are the deadliest cancers in children, highlighting the need for new therapies. The tumor-associated antigens (TAAs) WT1, PRAME and survivin are widely expressed by these tumors, and a manufacturing technique has been developed to target these intracellular TAAs using autologous, nongenetically engineered T cells.

Here we therefore conducted ReMIND, an open-label, phase 1 adaptive dose-finding study to determine the safety/feasibility of autologous, systemically administered trivalent T cells targeting WT1, PRAME and survivin in children with CNS tumors.

Eligible patients had newly diagnosed diffuse intrinsic pontine glioma without lymphodepletion (arm A, n = 16 enrolled, n = 11 infused) and relapsed/recurrent nonbrainstem CNS malignancies without (arm B, n = 28 enrolled, n = 18 infused) or with (arm C, n = 7 enrolled, n = 4 infused) lymphodepletion.

Primary end points were safety, feasibility and maximum tolerated dose determination; secondary end points included preliminary efficacy and immunobiological correlates, including in vivo TAA-T persistence and systemic immune activation. Dose level 3 (8 × 107 cells per m2 per dose) was determined as the maximum tolerated dose.

Treatment was well tolerated with fatigue and headache being the most common adverse events, although two possibly related serious adverse events of tumor swelling occurred. One grade 5 event in a patient with diffuse intrinsic pontine glioma with hydrocephalus, tumor edema and respiratory failure was categorized as a dose-limiting toxicity.

Median overall survival for arm A was 13.7 months from diagnosis (range, 6.2–32.0) and median progression-free survival for arms B/C was 5.0 months from infusion (range, 0.5–51.6).

Three patients in arms B/C are alive without disease at 31.8, 41.2 and 51.6 months without further treatment, including one complete response.

This trial met safety/feasibility primary end points with some preliminary signals of efficacy.  ..."

Nature Briefing: Translational Research

Four children with terminal brain cancer saved by new cell therapy "An experimental immunotherapy has beaten aggressive brain tumours in a handful of children, and a personalised version is now being tested on more patients"

Innovative cell therapy offers new hope for children with aggressive brain tumors (original news release)

Multi-antigen-targeting T cells in pediatric central nervous system tumors: a phase 1 trial (open access)

Magnetic resonance imaging scan of a vertical section of the head of a child with a glioma brain cancer (dark red, centre)

Blood test identifies tumor neighborhoods impacting immunotherapy

Good news! Cancer is history (soon)! This could be a breakthrough!

"In brief

• Stanford Medicine researchers developed a blood test predicting tumor microenvironments that influence cancer treatment decisions and patient outcomes.
• The study identifies nine shared cellular neighborhoods across cancers, aiding understanding of tumor responses to immunotherapy and potential therapies.
• This noninvasive approach transforms cancer treatment strategies, allowing real-time monitoring of tumor evolution and enabling personalized therapeutic interventions.

A simple blood test can reveal the geographic relationships among healthy cells surrounding a cancerous tumor, researchers ... have found. The test is the first noninvasive way to study what’s called the tumor microenvironment, which plays a critical role in determining how different patients – even those with similar tumors – fare after diagnosis and treatment. ...

the researchers identified nine cellular neighborhoods, or spatial ecotypes, that cancers of all types share and 

some of which correlate with a tumor’s response to immunotherapy and a patient’s prognosis.

Because the blood test can be performed repeatedly, clinicians may soon have real-time access to information about which types of therapies are likely to be most successful. ...

The researchers studied more than 100 tumor specimens from 10 distinct types of cancer using the tools they had developed to map patterns of gene expression in nine cell types at varying locations throughout the tumor.

They identified nine distinct spatial ecotypes, or neighborhoods, each roughly the diameter of a human hair. They found that patterns of spatial ecotypes were conserved among all the tumors they studied; some ecotypes were more likely to occur at the border of the tumor and healthy tissue, while others were more likely found deeper inside the tumor, for example. Several of the newly identified ecotypes correlated with whether a tumor would respond to immunotherapy – suggesting they could help guide clinical decision-making. ..."

From the abstract:

"Multicellular programs in the tumour microenvironment (TME) drive cancer pathogenesis and response to therapy but remain challenging to identify and profile clinically.

Here, we present a machine-learning framework for multi-analyte profiling of spatially dependent cell states and multicellular ecosystems, termed spatial ecotypes (SEs).

By integrating over 10 million single-cell and spot-level spatial transcriptomes from diverse human carcinomas and melanomas, we identified nine SEs with broad conservation, each of which has unique biology, geospatial features and clinical outcome associations, including several linked to immunotherapy response.

Notably, SEs were distinguishable by DNA methylation profiling and were recoverable from plasma cell-free DNA (cfDNA) using deep learning.

In cfDNA from nearly 100 patients with melanoma, SE levels exhibited striking associations with immunotherapy response.

Our data reveal fundamental units of TME organization and demonstrate a multimodal platform for profiling solid and liquid TMEs, with implications for improved risk stratification and therapy personalization."

Blood test identifies tumor neighborhoods impacting immunotherapy | Stanford Report "A new study shows how a noninvasive blood test can identify nine tumor neighborhoods, predicting microenvironments that affect patient responses to immunotherapy."

Non-invasive profiling of the tumour microenvironment with spatial ecotypes (open access)

Nine cellular environments, or spatial ecotypes, are shown here in a melanoma tumor. Spatial ecotypes, defined by the cellular interactions and the gene expression patterns of their cells, give clues about effective treatment options.

Fig. 1: Multimodal profiling of SEs in human cancer.

Fig. 2: Geospatial map of multicellular programs across cancers.

Cell-based microbots induce cell death only in cancer cells of multiple, different cancer types without affecting health cells

Good news! Cancer is history (soon)!

"Microrobots are a promising avenue for delivering medicines in the body ... A similarly tiny workhorse does a better job: our body’s own cells.

Researchers aimed to design a therapeutic that merged the drug delivery abilities of microrobots with the biological hunting abilities of natural cells.

They genetically engineered living human embryonic kidney cells to express a special molecule called tumor necrosis factor–related apoptosis-inducing ligand, or TRAIL.

When TRAIL binds to so-called “death receptors” in cancer cells, it sparks a series of signals that cause the cell to undergo programmed death.

Healthy cells, which have comparatively lower levels of death receptors, get left unharmed.

The researchers then outfitted the TRAIL-modified cells with tiny magnetic beads that enabled the team to magnetically navigate the cells to their targets. Across all kinds of cancer cells the team tested, including colon, brain, kidney, and ovarian cancer cells, the cell-based bot significantly harmed cancerous cells while leaving normal cells alive. ..."

"... These microrobots are built from living human kidney cells and also human fibroblasts that are genetically engineered to produce:

• TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)–a protein that selectively induces cancer cell death.
• GFP (green fluorescent protein)–a fluorescent marker used to visualize and track microrobots during navigation.

The engineered human cells are then attached to magnetic particles—tiny silica beads partially coated with a thin magnetic FePt layer. This design allows the microrobots to be remotely guided using magnetic fields.

After this fabrication process, the human cell-based microrobots can be magnetically controlled and directed toward target locations, where they release TRAIL as a therapeutic agent. Under external magnetic fields, they can be precisely guided to tumor sites, where they accumulate and act locally. ..."

From the abstract:

"Medical microrobots have strong potential for targeted therapeutic delivery; however, current systems achieve only physical targeting, and once at the target site, they are unable to distinguish healthy cells from cancerous ones because of the lack of biological selectivity.

Here, we present a biohybrid microrobot system that combines magnetic targeting with biological selectivity. The microrobots are derived from human embryonic kidney cells genetically engineered to produce tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a molecule that induces cancer cell death in multiple tumor types without damaging healthy cells.

Engineered cells are then conjugated to biocompatible magnetic Janus particles—silica beads half-coated with FePt nanofilms—to enable external magnetic control. With magnetic fields, the microrobots accumulate around the tumor spheroids and continuously release TRAIL for several days, leading to selective cancer cell death while avoiding damage to healthy cells.

This study combines microrobotics with genetically engineered cell therapies to achieve a targeted, prolonged, and cancer-selective therapeutic delivery."

ScienceAdviser

Human cell-based microrobots selectively kill cancer cells without harming healthy tissues

Genetically engineered human cell–based microrobots for selective cancer cell death (open access)

Figure 1. Fabrication of human cell-based microrobots.

Leukemia cells use a sugar-coated protein to hide from the immune system

Good news! Cancer is history (soon)!

"Highlights

• Study reveals previously unrecognized way for cancer to evade the immune system. 
• Other cancers could also be using sugar-coated proteins to shield themselves from immune attack.
• Findings suggest CD43 is a potential target for new cancer immunotherapies.

...

Now, researchers have identified a key part of the cancer’s disguise: a protein called CD43 on the surface of leukemia cells that is coated so heavily in sugar molecules that it forms a physical barrier, shielding the cells from immune attack. ..."

From the abstract of the Perspective:

"Immune cells continually detect, engulf, and destroy invasive microbes and cancer cells. This process, called phagocytosis, is carried out by macrophages that must distinguish between proengulfment signals and inhibitory (“don’t-eat-me”) warnings.

Cluster of differentiation 47 (CD47), a cell-surface receptor, is the archetypal don’t-eat-me signal.

Many cancers upregulate CD47 expression to escape phagocytosis, and CD47 blockade promotes phagocytosis of cancer cells in mice.

However, CD47 blockers have not shown clinical benefits in patients with acute myeloid leukemia (AML), an aggressive cancer of blood immune cells. This discrepancy has raised the possibility that the molecular programs that inhibit phagocytosis differ between mice and humans. On page 174 of this issue, Chung et al. report that the mechanisms that control macrophage function in human and mouse cells are indeed different. They also identify cluster of differentiation 43 (CD43) as a potential target for human AML treatment."

From the editor's summary and abstract:

"Editor’s summary

Phagocytosis is a process used by immune cells called macrophages to destroy pathogens and cellular debris.

Tumor cells can evade killing by macrophage-mediated phagocytosis by deploying decoy signals to the immune system.

Chung et al. performed a CRISPR screen of human acute myeloid leukemia (AML) cells to identify phagocytic regulators ... 

The surface protein CD43 was found to be coated in a high-density shield of sialic acid residues that effectively functioned as a “don’t eat me” signal to limit immune clearance.

Inactivation of CD43 function restored the ability of macrophages to phagocytize AML. Strategies that disable sialylated glycans may therefore have potential to enhance phagocytosis and targeting of AML. ...

Structured Abstract

INTRODUCTION

Macrophages in the tumor microenvironment exert antitumorigenic effects through phagocytosis and/or direct tumoricidal activity.

Phagocytosis of tumor cells occurs through both antibody-dependent cellular phagocytosis (ADCP) and antibody-independent cellular phagocytosis (AICP) mechanisms. Despite the strong evidence that macrophages can mediate tumor control in acute myeloid leukemia (AML) and other diseases, therapeutic agents that enhance macrophage phagocytosis, including anti-CD47 neutralizing antibodies, have not led to improved clinical outcomes. Thus, a more comprehensive understanding of the tumor-intrinsic factors that suppress human macrophage phagocytosis is needed.

RATIONALE

To systematically identify the key pathways that regulate phagocytosis by human macrophages, we performed genome-scale knockout CRISPR screens in human AML cell lines cocultured with human monocyte-derived macrophages.

RESULTS

We performed in vitro genome-wide loss-of-function CRISPR screens to identify the major pathways that regulate ADCP and AICP by human macrophages. Unexpectedly, we found that the classic “don’t eat me” signal CD47 has minimal impact on human macrophage phagocytosis.

By contrast, CD47 strongly suppressed mouse macrophage phagocytosis. Additionally, we identified the major histocompatibility class I complex (MHC class I) as the most potent negative regulator of ADCP.

By integrating results from the AICP and ADCP screens, we discovered that the O-linked glycosylation and sialylation pathways negatively regulate both AICP and ADCP.

CD43, a heavily sialylated cell surface glycoprotein, was the major mediator of the inhibitory effects of the O-linked glycosylation and sialylation pathways.

The inhibitory activity of CD43 was dependent on its sialic acid residues and the length of its ectodomain but independent of the canonical sialic acid–binding receptors SIGLEC-1, SIGLEC-7, and SIGLEC-9. CD43 expression reduced the avidity of interactions between immune effector cells and leukemia cells, consistent with a model where CD43 forms a steric or electrostatic glycocalyx barrier that reduces interactions with the leukemia cell surface.

We found that CD43 is overexpressed in AML patient samples, and inhibition of CD43 with antibodies enhances phagocytosis of AML cell lines and patient-derived samples.

Finally, we found that CD43 not only restrains human macrophage phagocytosis but also human natural killer (NK) and human T cell cytotoxicity.

CONCLUSION

The cell surface glycoprotein CD43 is a potent inhibitor of innate and adaptive antileukemic immunity. The inhibitory activity of CD43 on immune cells is dependent on posttranslational sialic acid modifications that are added through the O-linked glycosylation and sialylation pathways. Thus, sialylated CD43 is a potential therapeutic target for the treatment of AML."

Leukemia cells use a sugar-coated protein to hide from the immune system | Broad Institute "Targeting this protein, called CD43, could offer a new path to treatment for leukemia and other cancers."

The sialic shield of leukemia cells (Perspective, no public access)

Sialylated CD43 forms a glyco-immune barrier that restrains antileukemic immunity (no public access)

Genome-scale phagocytosis screens identify sialylated CD43 as a potent inhibitor of antileukemic immunity.

Why does the body deem some foods safe and others unsafe?

Amazing stuff!

"Highlights

• Scientists identify three new proteins, one each from soybean, corn, and wheat, that the body uses to determine oral tolerance—the opposite of food allergy
• They found that specialized immune cells called regulatory T cells interact with these proteins in the gut
• By understanding tolerance, researchers can better understand food allergies and begin to imagine future immunotherapies that promote tolerance rather than allergic reactions

...

identifies new bits of food proteins that tell gut immune cells when to tolerate certain foods. They found three of these protein segments, called epitopes—one each from soybean, corn, and wheat. These epitopes interact with specialized immune cells called regulatory T cells to inform that tolerance-or-rejection decision. ..."

"Editor’s summary

Immunological tolerance to dietary antigens is essential for preventing food allergies and digestive disorders such as celiac disease. However, the specific food-derived antigens that contribute to immune tolerance remain poorly described. Blum et al. mapped the dietary epitopes recognized by food-responsive T cell receptors (TCRs) derived from murine intestinal regulatory T (Treg) cells.

Seed storage proteins from corn, wheat, and soy, including the maize protein αZein, were targets of food-responsive Treg cell TCRs. αZein-specific Treg cells suppressed T cell responses to αZein ex vivo and after adoptive transfer into naive mice. These findings provide insight into the dietary components recognized by naturally occurring Treg cells that mediate oral tolerance. ...

Abstract

Food antigens elicit immune tolerance through the action of intestinal regulatory T (Treg) cells. Unlike food allergens, the proteins that mediate tolerance are mostly undescribed.

Here, we found that epitopes derived from seed storage proteins are targets of murine intestinal Treg cells, with the most frequent response targeting the C terminus of the maize protein alpha-zein.

A major histocompatibility complex (MHC) tetramer loaded with this antigen revealed that zein-specific T cells are predominantly intestinal Treg cells, develop concurrently with weaning, and constitute up to 2% of the peripheral Treg cell pool. Zein-responsive Treg cells repressed naïve T cell proliferation ex vivo, and prior dietary exposure resulted in a constrained response upon diverse inflammatory challenges in vivo, supporting a specific role for gut-resident Treg cells in suppressing systemic immune responses.

Our work reveals the development, immune-suppressive characteristics, and function of naturally occurring Treg cells that recognize dietary seed storage proteins, a previously undescribed class of antigens in oral tolerance."

Why does the body deem some foods safe and others unsafe? - Salk Institute for Biological Studies "Study co-led by scientist now at Salk Institute finds three new proteins that the body uses to determine “safe” foods, helping understand food tolerance and allergy"

Identification and characterization of dietary antigens in oral tolerance (no public access)

Greater precision for in vivo cancer-fighting CAR T cells

Good news! Cancer is history (soon)!

"Greater precision for in vivo CAR T

Researchers have invented a two-vector system that uses CRISPR–Cas9 gene editing to create in vivo cancer-fighting CAR T cells without accidentally targeting other cells. Leukaemia and multiple myeloma were eliminated in the mice treated with these precision in vivo CAR T cells, while more than half of mice with sarcoma went into remission. Biotech company Azalea Therapeutics is testing the approach in monkeys and hopes to trial the treatment in people by the end of next year."

From the abstract:

"Engineered T cells, reprogrammed to express chimeric antigen receptors (CAR) or T cell receptors (TCR), have transformed cancer treatment and are being explored as therapeutics for autoimmune and infectious diseases. Enhancing T cell function through genome editing, either by disrupting endogenous genes or precisely inserting DNA payloads, has shown considerable promise. However, the ex vivo manufacturing process is lengthy and costly, limiting accessibility of these therapies. In vivo generation of CAR T cells could overcome these barriers, but current methods rely either on transient expression with limited durability, or on random integration of DNA payloads that lack specificity.

Here we demonstrate that stable and cell-specific transgene expression can be achieved through in vivo site-specific integration of large DNA payloads. We developed a two-vector system to deliver CRISPR–Cas9 ribonucleoproteins and a DNA donor template, using enveloped delivery vehicles and adeno-associated viruses, respectively. We optimized both vectors for T cell-specific delivery and gene-targeting efficiency.

By integrating a CAR transgene into a T cell-specific locus, we generate therapeutic levels of CAR T cells in vivo in humanized mouse models of B cell aplasia, and haematological and solid malignancies. These findings offer a pathway to more efficient, precise and widely accessible T cell therapies."

Nature briefing cancer

CRISPR makes enhanced cancer-fighting immune cells inside mice "Gene-editing technique promises a potentially safer way to create CAR T cells with a simple injection."

A gene-editing method generates immunotherapeutic CAR T cells in the body "Laboratory-engineered immune cells called CAR T cells provide effective treatment for some cancers. Progress is being made towards creating these cells in vivo." (no public access)

In vivo site-specific engineering to reprogram T cells (open access)

Fig. 1: Co-delivery of Cas9-EDV and HDRT-AAV generates TRAC-CAR T cells in vitro and in vivo.

Previous efforts to create in vivo CAR T cells have involved viral vectors (that sometimes accidentally edit ‘bystander’ cells using retroviral transduction) or lipid nanoparticles (which deliver mRNA to T cells, creating transient expression of the CAR protein). To specifically target and permanently edit T cells, the team used two vectors: a CRISPR-Cas9 gene-editing system inside ‘enveloped delivery vehicles’, and viruses that transported the DNA coding for the CAR protein.

Faecal transplants boost immunotherapy

Good news! Fecal transplants keep on giving!

"Three trials provide compelling evidence that faecal microbiota transplantation (FMT) can boost the effectiveness of immunotherapy in advanced solid tumors ... in an analysis of three studies ... But challenges for safety, donor selection and product development remain.

Tumours partially or completely shrunk in 75% of FMT-treated people who underwent immunotherapy with melanoma, 80% of those with non-small cell lung cancer and 50% with metastatic renal cell carcinoma (RCC) across the studies. The only randomized, placebo-controlled trial, which evaluated immunotherapy plus an oral drug with or without FMT in individuals with metastatic RCC, did not find statistically significant 12-month progression-free survival. But it did find that FMT increased the proportion of people whose tumours shrunk (52% versus 32%)."

Nature Briefing: Translational Research

Microbiome modulation in cancer immunotherapy (no public access) "Three landmark trials confirm that fecal microbiota transplantation is a promising approach to enhancing immunotherapy efficacy in advanced solid tumors. The trials also provide insights with major implications for microbiome therapeutic development."

Three studies suggest that FMT improves immunotherapy responsiveness not only by bolstering the growth of good bacteria, which improves the microbiome to help the immune system respond to cancer, but also by killing off bad bacteria.

A new immunotherapy approach could work for many types of cancer

Good news! Cancer is history (soon)!

"... The key to their approach is reversing a “brake” that cancer cells engage to prevent immune cells from launching an attack. This brake is controlled by sugar molecules known as glycans that are found on the surface of cancer cells.

By blocking those glycans with molecules called lectins, the researchers showed they could dramatically boost the immune system’s response to cancer cells. To achieve this, they created multifunctional molecules known as AbLecs, which combine a lectin with a tumor-targeting antibody. ...

Glycans are found on nearly all living cells, but tumor cells often express glycans that are not found on healthy cells, including glycans that contain a monosaccharide called sialic acid. When sialic acids bind to lectin receptors, located on immune cells, it turns on an immunosuppressive pathway in the immune cells. These lectins that bind to sialic acid are known as Siglecs. ...

In this study, the researchers designed an AbLec based on the antibody trastuzumab, which binds to HER2 and is approved as a cancer therapy to treat breast, stomach, and colorectal cancers. To form the AbLec, they replaced one arm of the antibody with a lectin, either Siglec-7 or Siglec-9.

Tests using cells grown in the lab showed that this AbLec rewired immune cells to attack and destroy cancer cells. ..."

From the abstract:

"Despite the curative potential of checkpoint blockade immunotherapy, many patients remain unresponsive to existing treatments.

Glyco-immune checkpoints, which involve interactions of cell-surface glycans with lectin, or glycan-binding, immunoreceptors, have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer.

Here, we describe antibody-lectin chimeras (AbLecs), a modular system for glyco-immune checkpoint blockade. AbLecs are bispecific antibody-like molecules comprising a cell-targeting antibody domain and a lectin ‘decoy receptor’ domain that directly binds glycans and blocks their ability to engage inhibitory lectin receptors.

AbLecs potentiate cancer cell destruction by primary human immune cells in vitro and reduce tumour burden in a humanized, immunocompetent mouse model, outperforming most existing therapies and combinations tested.

By targeting a distinct axis of immunological regulation, AbLecs synergize with blockade of established immune checkpoints.

AbLecs can be readily designed to target numerous tumours and immune cell subsets as well as glyco-immune checkpoints, thus representing a potential modality for cancer immunotherapy."

A new immunotherapy approach could work for many types of cancer | MIT News | Massachusetts Institute of Technology "Using new molecules that block an immune checkpoint, researchers showed they could stimulate a strong anti-tumor immune response."

Antibody-lectin chimeras for glyco-immune checkpoint blockade (open access)

Fig. 1: AbLecs enable targeted glyco-immune checkpoint blockade.

Patrick Soon-Shiong's cancer drug Anktiva just approved by Saudi Arabia FDA

Food for thought! Is the US FDA too cautious? Ist Saudi Arabia becoming a Mecca for Western drugs with limited approval and medical tourism?

Pioneering new CAR T cell therapy reverses incurable blood cancer in 7 out of 11 patients (children and adults)

Good news! Cancer is history (soon)!

"Designer CAR Ts keep blood cancer at bay

Switching out letters in the genetic code of CAR T cells has put 7 out of 11 people with a type of blood cancer known as acute lymphoblastic leukemia into remission. The pioneering treatment uses CRISPR to make three base edits in the DNA of donor CAR T cells. These edits make it possible for the CAR T cells to seek out and destroy cancerous T cells while shielding themselves from attack from the immune system and chemotherapy. ..."

From the abstract:

"Abstract

Background

CD7 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory T-cell acute lymphoblastic leukemia (ALL). Supportive results of first-in-human studies of base-edited anti-CD7 CAR (BE-CAR7) T cells with triple C→T deamination-mediated knockouts of TCRαβ, CD52, and CD7 have been reported previously.

Methods

In a phase 1 study, we administered BE-CAR7 T cells to children (≤16 years of age) with relapsed or refractory T-cell ALL after they had undergone lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab. Adults with compassionate-use access arrangements were also eligible. Patients who had remission by day 28 after the BE-CAR7 T-cell infusion proceeded to allogeneic hematopoietic stem-cell transplantation. The primary outcome was safety. Secondary outcomes included duration of remission, disease-free survival, and overall survival.

Results

BE-CAR7 T cells were administered to 9 children, as well as to 2 adults who were treated under compassionate-use access arrangements. Lymphodepletion and BE-CAR7 infusions did not lead to unacceptable adverse events, and circulating CAR7 T cells were detected in all the patients.

Complications included cytokine release syndrome of grades 1 through 4, transient rashes, multilineage cytopenia, and opportunistic infections.

All the patients had complete morphologic remission with incomplete count recovery at day 28.

Nine patients (82%) had deep remission (according to flow cytometry or polymerase-chain-reaction assay) that allowed them to proceed to stem-cell transplantation, and 2 patients with quantifiable minimal residual disease in bone marrow received palliative care.
Transplantation eliminated remaining BE-CAR7 T cells and supported donor-derived, multilineage reconstitution.
Viral reactivations were frequent, and 3 patients had clinically significant virus-related complications after transplantation.
Overall, 7 of the 11 patients (64%) who received the investigational therapy were in ongoing remission at 3 to 36 months after transplantation, and leukemia with loss of CD7 expression was documented in 2 patients.

Conclusions

Universal BE-CAR7 T cells induced leukemic remission in patients with relapsed or refractory T-cell ALL, thus allowing successful allogeneic hematopoietic stem-cell transplantation in most of the patients. ..."

Nature Briefing: Cancer

Pioneering new treatment reverses incurable blood cancer in some patients

Universal Base-Edited CAR7 T Cells for T-Cell Acute Lymphoblastic Leukemia (no public access)

Revolutionary gene therapy brings hope of leukaemia cure

Good news! Very recommendable! Cancer is history (soon)! The surviving teenage girl said she would go into biomedical research!

How antibody therapy clears Alzheimer's plaques: Key immune mechanism identified

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"Lecanemab, sold under the name Leqembi, is a monoclonal antibody therapy for Alzheimer's disease that clears toxic amyloid plaques and delays cognitive decline. ...

They showed that the "Fc fragment" of this monoclonal antibody is essential for engaging microglia—the immune cells of the brain—thus initiating the cellular machinery needed for plaque removal. This is the first direct mechanistic explanation for how this class of therapies works. It clarifies uncertainties in the field and offers a blueprint for developing safer, more effective Alzheimer's treatments.  ...

They identified key cellular machinery needed to clear the amyloid plaques: namely, phagocytosis and lysosomal activity.

Without the Fc fragment, none of these critical cellular processes were triggered. ...  uncovered a microglial gene program, marked by strong expression of the gene SPP1.  ..."

From the abstract:

"Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action.

Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions.

Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding.

Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation.

Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance.

These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer’s disease."

How antibody therapy clears Alzheimer's plaques: Key immune mechanism identified

New immune process identified that may alleviate Alzheimer's disease (original news release)

The Alzheimer’s therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia (open access)

Fig. 1: Lecanemab drives strong transcriptional changes in human microglia associated with Aβ plaques.

Fig. 2: Lecanemab alleviates Aβ pathology by triggering effector functions in the microglia.

New nanoparticles stimulate the immune system to attack ovarian tumors

Good news! Cancer is history (soon)! This new therapy attacks metastatic tumors and has memory to prevent recurrence!

"... To elicit a better response, MIT researchers have designed new nanoparticles that can deliver an immune-stimulating molecule called IL-12 directly to ovarian tumors. When given along with immunotherapy drugs called checkpoint inhibitors, IL-12 helps the immune system launch an attack on cancer cells.

Studying a mouse model of ovarian cancer, the researchers showed that this combination treatment could eliminate metastatic tumors in more than 80 percent of the mice. When the mice were later injected with more cancer cells, to simulate tumor recurrence, their immune cells remembered the tumor proteins and cleared them again. ...

In the new study, the researchers modified the particles so that IL-12 would be released more gradually, over about a week. They achieved this by using a different chemical linker to attach IL-12 to the particles. ...

To make sure that the particles get to the right place, the researchers coat them with a layer of a polymer called poly-L-glutamate (PLE), which helps them directly target ovarian tumor cells. Once they reach the tumors, the particles bind to the cancer cell surfaces, where they gradually release their payload and activate nearby T cells. ..."

From the abstract:

"Immunotherapies such as immune checkpoint inhibitors are effective in treating several advanced cancers, but these treatments have had limited success in metastatic ovarian cancer.

Here we engineered liposomal nanoparticles carrying a poly-ʟ-arginine/poly-ʟ-glutamate coating that promotes their binding and retention on the surface of ovarian cancer cells. Covalent anchoring of the potent immunostimulatory cytokine interleukin-12 (IL-12) to phospholipid head groups of the liposome core enabled the polymer-coated particles to concentrate IL-12 in disseminated ovarian cancer tumours following intraperitoneal administration. Shedding of the layer-by-layer coating and serum-protein-mediated extraction of IL-12-conjugated lipids from the liposomal core over time enabled IL-12 to disseminate in the tumour bed following rapid nanoparticle localization in tumour nodules.

Optimized IL-12-polymer-coated nanoparticles promoted robust T cell accumulation in ascites and tumours in mouse models, extending survival compared with free IL-12 and sensitizing tumours to immune checkpoint inhibitors, eliciting strong immune responses and immune memory.

Overall, these findings support the potential of these polymer-coated nanoparticles for the sustained delivery of IL-12 to disseminated metastatic ovarian cancer."

New nanoparticles stimulate the immune system to attack ovarian tumors | MIT News | Massachusetts Institute of Technology "Targeted particles carrying the cytokine IL-12 can jump-start T cells, allowing them to clear tumors while avoiding side effects."

IL-12-releasing nanoparticles for effective immunotherapy of metastatic ovarian cancer

Fig. 3: Mal LbL NPs efficiently target and deliver IL-12 to OC tumour nodules.

Scientists develop one-product-fits-all immunotherapy for pancreatic cancer

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"Key takeaways:

• UCLA researchers have developed a CAR-NKT cell therapy that has shown to be more effective than current immunotherapies at fighting tumors in several different mouse models of pancreatic cancer.
• Unlike current personalized cell therapies, which require weeks to manufacture, this novel therapy can be mass-produced and stored ready-to-use at a fraction of the cost.
• With all preclinical studies now complete, the team is preparing to submit applications to the Food and Drug Administration to begin clinical trials.

...

Now, ... researchers have engineered a novel immunotherapy that could offer new hope for a disease that has remained stubbornly resistant to treatment advances for decades. In a study ... the team details how the therapy, called CAR-NKT cell therapy, can track down and destroy pancreatic tumors even after they’ve metastasized to other organs. ..."

From the significance and abstract:

"Significance

Pancreatic cancer (PC) is one of the deadliest cancers, often diagnosed at advanced, hard-to-treat stages. Current cell-based therapies like CAR-T cells face major hurdles, including tumor variability, immune escape, and limited scalability. In this study, we developed an off-the-shelf immunotherapy using gene-engineered natural killer T cells derived from stem cells—called Allo15MCAR-NKT cells. These cells target pancreatic tumors through multiple killing mechanisms, resist immune exhaustion, and avoid rejection by the patient’s immune system. In preclinical models, they effectively controlled tumor growth and spread. This work offers a promising step toward scalable, next-generation immunotherapy for PC, with the potential to address current treatment limitations and improve outcomes for patients with advanced disease.

Abstract

Pancreatic cancer (PC) remains one of the leading causes of cancer-related mortality worldwide. The majority of patients are diagnosed at advanced stages, with over 50% presenting with metastatic disease at the time of diagnosis. Although chimeric antigen receptor (CAR)-T cell therapy has shown promise in targeting PC, its clinical efficacy remains limited due to several critical challenges. These include tumor antigen heterogeneity, antigen loss or escape mechanisms, functional exhaustion of CAR-T cells within the tumor microenvironment, as well as inherent limitations of autologous approaches such as high manufacturing costs, prolonged production timelines, and restricted scalability.

To address these challenges, we developed allogeneic IL-15–enhanced, mesothelin-specific CAR-engineered invariant natural killer T (Allo15MCAR-NKT) cells through gene engineering of human hematopoietic stem and progenitor cells (HSPCs) using a clinically guided culture method.

These Allo15MCAR-NKT cells exhibited robust and multifaceted antitumor activity against PC, driven by both CAR and NK receptor–mediated cytotoxic mechanisms.

In orthotopic and metastatic human PC xenograft models, Allo15MCAR-NKT cells demonstrated superior tumor control, enhanced trafficking and infiltration into tumor sites, sustained effector and cytotoxic phenotypes, and reduced expression of exhaustion markers.

Importantly, Allo15MCAR-NKT cells demonstrated a favorable safety profile, characterized by the absence of graft-versus-host disease and minimal cytokine release syndrome.

Collectively, these findings validate Allo15MCAR-NKT cells as a promising next-generation, off-the-shelf immunotherapeutic approach for PC, with the potential to overcome critical challenges including tumor heterogeneity, immune evasion, and therapeutic resistance, especially in the context of metastatic disease."

UCLA scientists develop one-product-fits-all immunotherapy for pancreatic cancer | UCLA

Targeting orthotopic and metastatic pancreatic cancer with allogeneic stem cell–engineered mesothelin-redirected CAR-NKT cells (open access)

Microscopy image showing a stem cell-engineered CAR-NKT cell (blue) attacking a human solid tumor cell (magenta).

Fig. 1 Generation and characterization of HSPC-engineered allogeneic IL-15-enhanced MCAR-NKT (Allo15MCAR-NKT) cells.

Reversing Fibrosis: New Research Provides Insight for Novel Therapies

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"Yale School of Medicine (YSM) researchers have made key breakthroughs in understanding how to treat fibrotic diseases such as scleroderma and graft-versus-host disease.

Fibrotic diseases are a group of conditions—often autoimmune—characterized by excessive tissue scarring. They can drastically hinder patients’ quality of life, and in some cases, they can be life-threatening—fibrosis contributes to approximately 45% of all deaths in developed nations. However, there are no effective treatments.

Now, in a study ... researchers have developed a monoclonal antibody that is showing promise as a new therapy for patients. And in a [second] ... study, the same team discovered a signaling pathway that may be mediating fibrosis and could be a target for future therapies. ...

Then, the team tested their anti-EREG antibody in humanized mouse models and skin biopsies from patients and found that inhibiting epiregulin reduced biomarkers associated with fibrosis. These findings suggest that the therapeutic antibody could be a promising new therapy for patients with various types of fibrotic conditions. ...

In a second recent study, the researchers aimed to further understand mechanisms that differentiate fibrotic and non-fibrotic skin diseases. The team compared single-cell RNA sequencing data from seven different inflammatory skin diseases. Some of the diseases, like atopic dermatitis and psoriasis, were associated with redness and scaling, but not fibrosis. They also analyzed data from patients with fibrotic diseases such as scleroderma, graft-versus-host disease, and lupus.

Their analyses revealed that fibrotic diseases were associated with greater activity of a protein called STAT1 in fibroblasts, the key cell type that’s hyperactivated in fibrotic diseases. To better understand how STAT1 interacts with the EGFR signaling pathway to drive fibrosis, the researchers developed mouse models that lacked STAT1. When the team activated EGFR, they found that mice without STAT1 showed less fibrosis compared to regular animal models.

“If we activate EGFR by inducing injury when there’s no STAT1 present, none of the fibrotic genes are activated,” ...

The researchers conducted further experiments on cultured fibroblasts in vitro which confirmed that STAT1 was required for the onset of fibrosis. ...

Importantly, the upregulation of epiregulin activation of EGFR-STAT1 pathway isn’t always active—it’s only switched on under specific conditions such as the presence of injury or inflammation. ..."

"Key Points

• New fully human anti-EREG therapeutic antibody is highly developable and demonstrates antifibrotic capabilities in vivo.
• Sclerotic GvHD and SSc share EREG-TNC-TLR4 signaling axis that is reduced by anti-EREG treatment in patient skin explants.

..."

From the abstract:

"Chronic inflammatory skin diseases affect the health of millions of people worldwide, and those that feature fibrosis are refractory to treatments. The signals that determine whether fibrosis occurs during chronic skin inflammation are poorly understood.

We generated a scRNA-seq atlas of seven inflammatory skin diseases and their healthy controls.

Diseases with fibrosis demonstrate higher expression and activity of STAT1 in fibroblasts.

Fibroblast STAT1 is required for skin fibrosis development in mice. STAT1 activation promotes a fibrotic gene expression profile which can be activated directly by EGFR in a JAK-independent manner and abrogated by genetic and pharmacologic STAT1 inhibition.

The EGFR-STAT1 pathway is stimulated by high affinity EGFR ligands expressed by activated keratinocytes, suggesting keratinocyte-derived signals as triggers of skin fibrosis.

In sum, fibroinflammatory skin diseases are characterized by fibroblast EGFR-STAT1 signaling that controls expression of fibrotic genes, elucidating an interferon independent function of STAT1 to mediate fibrotic skin diseases."

Reversing Fibrosis: New Research Provides Insight for Novel Therapies | Yale School of Medicine

Sclerotic GVHD and Scleroderma Share Dysregulated Gene Expression that is Ameliorated by EREG Therapeutic Antibody (no public access)

EGFR-STAT1 pathway drives fibrosis initiation in fibroinflammatory skin diseases (open access)

Fig. 1: Integrated inflammatory skin disease atlas shows upregulated STAT1 expression in SFRP2+ fibroblasts.

Fig. 2: SCENIC analysis of fibroblasts identifies STAT1 as a central regulon in fibrotic skin.