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.

Why immune responses to vaccines vary from person to person and how to predict a vaccine response before vaccination

Good news! A still open question how much of the humoral immune response is inherited and how much is due to lifetime training of the immune system of an individual.

"... In blood samples from more than 4,000 people, ASU researchers and their colleagues measured antibodies against 185 antigens—targets recognized by the immune system, including those from common viruses and bacteria as well as targets associated with autoimmune diseases.

They then used artificial intelligence to analyze patterns in samples collected before and after COVID-19 vaccination, identifying antibody signatures that helped distinguish strong vaccine responders from weak ones.

The research opens a possible path toward more personalized vaccination strategies.

"What our study found is that certain biomarkers, when analyzed with AI, can predict who is likely to respond well to a vaccine, even before they receive it. This suggests that some people may be more immune-ready than others," ..."

From the highlights and abstract:

"Highlights

• Pre-existing antibodies to common microbes predict new vaccine response robustness

• These sentinel antibodies are stable markers of humoral immune readiness

• AI models use global antibody profiles to stratify high and low vaccine responders

• Blunted vaccine responses occur in both immunosuppressed and healthy individuals

Summary

Predicting which individuals will mount poor antibody responses before vaccination could improve personalized vaccination strategies.

Here, we conducted a national longitudinal study of humoral immune responses to 185 antigens, including SARS-CoV-2 (n = 3), common microbial pathogens (n = 157), and autoantigens (n = 25), in 1,644 immunosuppressed patients and 2,445 healthy individuals before and after COVID-19 vaccination.

Although blunted COVID-19 vaccine responses were more frequent in solid organ transplant recipients and individuals with multiple myeloma, autoimmune disease, inflammatory bowel disease, and human immunodeficiency virus, responses were highly heterogeneous within every cohort, and approximately 5%–6% of healthy individuals also mounted weak responses.

Pre-existing antibodies to common microbes, including Staphylococcus aureus, respiratory syncytial virus, and human respirovirus 3, consistently predicted post-vaccination antibody responses in both healthy and immunosuppressed populations.

These broadly prevalent antimicrobial antibodies represent sentinel antibodies that may serve as biomarkers of system-level humoral immune competence.

Using global antimicrobial antibody profiles, we developed a deep-learning predictive model that stratified individuals according to their likelihood of mounting blunted vaccine responses.

Together, these findings identify pre-existing antimicrobial antibody profiles as scalable biomarkers of humoral immune responsiveness and provide a framework for predicting vaccine responses before immunization."

Why immune responses to vaccines vary from person to person

Why immune responses to vaccines vary from person to person (original news release) "Study finds past immune encounters may predict future vaccine response"

Pre-vaccine sentinel antibodies predict blunted vaccine responses (open access)

Graphical abstract

Figure 2 The multiplexed humoral immune profiling of 8,687 individual samples among seven cohorts

Figure 7 Pre-existing antimicrobial antibody profiles predict healthy individuals with low vaccine response to COVID-19 booster

UCLA opens Center for Advanced Biotherapies, expanding capacity to develop and deliver personalized cell and gene therapies

Good news!

"Key takeaways 

• UCLA has opened the Center for Advanced Biotherapies, a 14,000-square-foot FDA-compliant manufacturing facility that nearly doubles the institution’s capacity to produce cell and gene therapies for patients enrolled in clinical trials.
• The facility — built with support from the National Institutes of Health and the California Institute for Regenerative Medicine — is equipped to manufacture a broad range of personalized treatments, from cancer vaccines to stem cell gene therapies.
• The facility’s proximity to UCLA’s hospitals and clinics means researchers can move a therapy from the manufacturing suite to an early phase clinical trial patient’s bedside the same day.

For 30 years, the UCLA Human Gene and Cell Therapy Facility has been the quiet engine behind some of the university’s most ambitious clinical research, supporting more than 25 clinical trials and producing over 300 personalized therapy products for patients with cancer, HIV/AIDS, sickle cell disease and rare genetic disorders. But the science consistently exceeded what the space was designed for. ...

The center features 10 cleanrooms, including seven manufacturing suites designed to run multiple therapies simultaneously, two bioengineering rooms built for large-scale equipment, including bioreactors and 3D printers, and a dedicated suite for viral vector manufacturing. A centralized quality control laboratory supports comprehensive product testing and release.  ..."

UCLA opens Center for Advanced Biotherapies, expanding capacity to develop and deliver cell and gene therapies | UCLA

Three researchers in full white protective suits and gloves work inside a sterile cleanroom laboratory, viewed through a glass door.

Can This 3d printed, personalized “Living Knee” Revolutionize Joint Replacement due to osteoarhthrits?

Good news! This seems to be a promising approach! A company was already formed to commercialize this new orthopedic joint. It uses patient stem cells to build new cartilage.

"... to create a new biological knee joint that can last a lifetime, expand joint surgery to younger patients, and provide a better joint for all patients.

Two years into the project, ARPA-H has now given the team the green light to move into the second phase of development and begin preclinical testing of their “living knee” implant, called NOVAKnee. ...

“Our decades of research studying cartilage have shown that no other material has the same joint lubrication or load-bearing properties of articular cartilage. Based on this, we decided that we needed a strategy to regenerate a living knee, rather than simply replacing it,” ...

The Columbia design for this new joint looks like current metal and plastic replacement joints and will be surgically implanted with the same procedures. But NOVAKnee is a living, 3D-printed human organ, created with a biodegradable scaffolding material infused with stem cells. After implantation, the cells will regenerate the joint’s natural cartilage and bone tissues as the scaffold disappears. 

The team identified new biomaterials and used them to design an implant that can sustain the loading of the human knee. The implant contains combinations of biomaterials to make femoral- and tibial-shaped implants, sized to the patient’s knee. Then it gets seeded with cartilage and bone cells, derived from stem cells either from the patient’s own body (lipoaspirate from the abdomen) or from adult inducible pluripotent stem cells. ...

To accelerate this breakthrough technology's path to patients, NOVAJoint Orthopedics ... has been established as an independent company committed to commercializing the NOVAKnee implant and extending the technology across orthopedic applications. ..."

Can This “Living Knee” Revolutionize Joint Replacement? | Columbia University Irving Medical Center

NOVAJoint Orthopedics

Personalized Therapeutic Vaccine induced the Immune System to Fight Kidney Cancer

Good news! Cancer is history (soon)!

"All nine patients with advanced kidney cancer in an early-phase trial of a personalized therapeutic vaccine had successful anti-cancer immune responses and remained cancer-free approximately three years after treatment. A therapeutic vaccine is used after disease sets in, aiming to induce immunity to alter the course of disease.

Each patient’s vaccine was created with information found by examining the DNA and RNA in the patient’s tumor, which identified mutations that were only found in the cancer. Like all vaccines, personalized cancer vaccines (PCVs) train the body’s immune system to recognize and destroy a threat. In this case, the threat was any cancer cells remaining after surgery. ..."

From the abstract:

"Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient’s tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden.

Here we conducted a phase I trial ... to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine.

At a median follow-up of 40.2 months after surgery, none of the 9 participants enrolled in the study had a recurrence of RCC.

No dose-limiting toxicities were observed. All patients generated T cell immune responses against the PCV antigens, including to RCC driver mutations in VHL, PBRM1, BAP1, KDM5C and PIK3CA. Following vaccination, there was a durable expansion of peripheral T cell clones. Moreover, T cell reactivity against autologous tumours was detected in seven out of nine patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations and can induce antitumor immunity. These observations, in conjunction with the absence of recurrence in all nine vaccinated patients, highlights the promise of PCVs as effective adjuvant therapy in RCC."

Personalized Therapeutic Vaccine ‘Steers’ the Immune System to Fight Kidney Cancer < Yale School of Medicine

A neoantigen vaccine generates antitumour immunity in renal cell carcinoma (open access)

Fig. 1: Vaccine manufacturing process and clinical outcomes.

This toilet company wants to put a $500 laboratory in your toilet bowl

This is an interesting idea whose time has come! As time goes by and consumer acceptance increases, the price will surely fall!

The earlier a medical condition is discovered the better the outcomes!

Like smartphones are more and more becoming medical round the clock monitors of our health!

This toilet company wants to put a $500 laboratory in your toilet bowl It's like taking a medical sample every day.