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Hodgkin lymphoma cells

T-cell therapy alone or combined with nivolumab is safe and persistent in attacking Hodgkin’s lymphoma cells

Hodgkin lymphoma cells

Hodgkin’s lymphoma is a type of cancer that attacks part of the immune system and expresses tumor-associated antigens (TAA) that are potential targets for cellular therapies.

It is safe for patients with relapsed or refractory Hodgkin’s lymphoma (HL) to receive a novel tumor-associated antigen specific T-cell therapy (TAA-T) either alone or combined with a checkpoint inhibitor, nivolumab — a medication used to treat several types of cancer. The study, published in Blood Advances, further suggests that nivolumab aids in T-cell persistence and expansion to ultimately enhance anti-tumor activity. This offers a potential option for patients who do not have a durable remission with checkpoint inhibitors alone or are at a high risk of relapse after a transplant.

“The fact that this combination therapy is so safe was very encouraging for the treatment of patients with lymphomas,” said Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National Hospital. “In addition, this data allows us to consider this combination immunotherapy for other patients, including those with solid tumors.”

HL is a type of cancer that attacks part of the immune system and expresses tumor-associated antigens (TAA) that are potential targets for cellular therapies. While it may affect children and adults, it is most common in those who are between 20 and 40 years old. The survival rate for this condition has improved due to scientific advances.

A new approach in cancer therapy is the use of “checkpoint inhibitors,” which are a class of drugs that block some of the inhibitory pathways of the immune system to unleash a powerful tumor killing immune response. Similarly, T-cell therapies have also shown to enhance anti-tumor immune response. Therefore, combining these novel immune therapies is an attractive and targeted alternative to conventional untargeted therapies – such as chemotherapy and radiation – which not only kill the tumor cells but also can kill healthy cells and tissues.

“In five to 10 years we can get rid of chemotherapy and radiation therapy and have an immunotherapy focused treatment for this disease,” said Dr. Bollard.

To determine the safety of infusing TAA-T with and without checkpoint inhibitors, eight patients were infused with TAA-specific T-cell products manufactured from their own blood. Two other patients received TAA-T generated from matched healthy donors as adjuvant therapy after hematopoietic stem cell transplant. According to Dave et al., the TAA-T infusions were safe and patients who received TAA-T as adjuvant therapy after transplant remained in continued remission for over two years.

Of the eight patients with active disease, one patient had a complete response, and seven had stable disease at three months, three of whom remained with stable disease during the first year.

“Treating Hodgkin’s lymphoma with cellular therapy has not yet achieved the same success that we have seen for other lymphoma subtypes,” said Keri Toner, M.D., attending physician at Children’s National. “This study brings us closer to overcoming some of the current barriers by developing methods to improve the persistence and function of the tumor-specific T-cells.”

This study builds upon the researchers’ latest findings in another study, which demonstrated that TAA-T manufactured from patients were safe and associated with prolonged time to progression in solid tumors.

“The addition of a checkpoint inhibitor like Nivolumab to the TAA-T treatment is a powerful next step, but previously, the safety of this combination was unknown,” said Patrick Hanley, Ph.D., chief and director of the Cellular Therapy Program at Children’s National, leader of the GMP laboratory and co-author of the study. “Now that we have demonstrated a safety profile, the next step will be to evaluate the efficacy of this combination in a larger subset of patients.”

A transient low-dose MEKi treatment in a pre-clinical model prevents NF1-OPG formation

Using targeted signaling pathway therapy to prevent pediatric glioma formation

Researchers at Children’s National Hospital identified a vulnerability in a developmental signaling pathway that can be hijacked to drive pediatric low-grade glioma (pLGG) formation, according to a pre-clinical study published in Developmental Cell. The study demonstrated that targeted treatment prevents tumor formation, long before irreversible damage to the optic nerve can cause permanent loss of vision. This finding will inform chemo-prevention therapeutic trials in the future.

Brain tumors are the most common solid tumors in children, the most prevalent of which are pLGGs. Approximately 10% to 15% of pLGGs arise in patients with the familial cancer predisposition syndrome known as neurofibromatosis type 1 (NF1). This is a genetic condition that increases risks of developing tumors along the nerves and in the brain.

Nearly 20% of children with NF1 develop pLGGs along the optic pathway, also known as NF1-associated optic pathway glioma (NF1-OPG). Despite many advances in cancer therapy, there are no definitive therapies available that prevent or alleviate the neurological deficits (i.e. vision loss) and that could improve the quality of life.

“The evidence presented can inform chemoprevention therapeutic trials for children with NF1-OPG,” said Yuan Zhu, Ph.D., scientific director and Gilbert Family Endowed professor at the Gilbert Family Neurofibromatosis Institute and associate director of the Center for Cancer and Immunology Research, both part of Children’s National. “This therapeutic strategy may also be applicable to children with the developmental disorders that are at high risk of developing pediatric tumors, such as other RASopathies.”

The mechanism of vulnerability to pLGGs during development is not fully understood. It has been implied that the cell population of origin for this debilitating tumor is transiently proliferative during development. The NF1 gene produces a protein that helps regulate normal cell proliferation, survival and differentiation by inhibiting MEK/ERK signaling. When there is loss of function in NF1, it abnormally activates the MEK/ERK signaling pathway and leads to tumor formation.

Certain cells that exist transiently during the normal development of the brain and optic nerve are vulnerable to tumor formation because they depend on the MEK/ERK signaling. In this study, researchers in Zhu’s lab identified cells that were MEK/ERK pathway dependent and grew during a transient developmental window as the lineage-of-origin for NF1-OPG in the optic nerve. The researchers used a genetically engineered pre-clinical model to design a transient, low-dose chemo-preventative strategy, which prevented these tumors entirely.

“When we provided a dose-dependent inhibition of MEK/ERK signaling, it rescued the emergence and increase of brain lipid binding protein-expressing (BLBP+) migrating GPs glial progenitors, preventing NF1-OPG formation,” wrote Jecrois et al. “Equally importantly, the degree of ERK inhibition required for preventing NF1-OPG formation also greatly improved the health and survival of the NF1-deficient model.”

Ongoing clinical trials using MEK inhibitors (MEKi) are being performed for children as young as 1 month old. Thus, it becomes increasingly feasible to design a chemo-preventative trial using a MEKi to treat children with NF1. These treatment paradigms may have the potential to not only prevent OPG formation, but also other NF1-associated and RASopathies-associated developmental defects and tumors.

A transient low-dose MEKi treatment in a pre-clinical model prevents NF1-OPG formation

A transient low-dose MEKi treatment in a pre-clinical model prevents NF1-OPG formation. The middle panels highlighted by a red dashed box show an OPG in the optic nerve (arrows, top), exhibiting abnormal triply-labeled tumor cells, inflammation and nerve damage (the bottom three panels), which are absent in the normal (left panels) or MEKi-treated Nf1-deficient optic nerves (right panels). [Credit: Jecrois et al., Developmental Cell, (2021)]

tubes filled with pink liquid

Manufacturing technologies lag behind breakthroughs in CAR-T cancer treatment

tubes filled with pink liquid

Drug companies around the country are banking on the cutting-edge cancer treatments known as CAR-T, but many manufacturing processes are holding back the treatment from reaching the market. With the success of CAR-T, which essentially re-trains T Cells to identify and target the cancer-causing cells, many manufacturers still need to catch up in the development process.

Currently, there are nearly 700 CAR-T studies in the database ClinicalTrials.gov, including 152 industry-sponsored trials that are active, recruiting or enrolling by invitation. According to market research firm, Coherent Market Insights, they predict the CAR-T market will grow to $8 billion worldwide by 2028 from $168 million in 2018.

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children’s National Health System, was featured in a recent Bloomberg Law article stating that academics, industry participants and medical product regulators are trying to catch up with the technology and determine the best standards for developing these products. Although this is an exciting and positive time in the field of oncology, it also presents a big learning curve.

Making these cells requires extracting patients T cells. They are then genetically engineered in a laboratory to produce proteins that allow them to identify cancer-causing cells. The new cells are then multiplied and then reintroduced into the body to kill off the cancer cells. The entire process can take a few weeks to complete.

“This is not a drug,” Bollard said. “This is a living biologic, and it comes from the patient and individuals. There’s so much variability.”

Along with manufacturing challenges, the outlook on creating more therapies is looking good. The FDA predicts that it will be approving 10 to 20 gene therapy products a year by 2025. Other companies are working to develop a manufacturing platform that can help reduce the complexity of the current system and ultimately make CAR-T manufacturing easier to scale.