A Leap Forward in Research on CAR T-cell Therapy

Cell

Chimeric antigen receptor (CAR) T cell therapy is an arising and extremely promising cellular immunotherapy approach to treat cancer. This innovative approach takes advantage of the characteristics of T cells, which are a key component of our immune system. These T cells, hundreds of billions of which circulate through our bodies at any given time, are capable of detecting and destroying cells that have been damaged, infected with viruses, or malignant.

Our normal T cells usually perform an excellent job of safeguarding us from threats, but they are not flawless. Fortunately, CAR T cell techniques can boost the effectiveness of these already potent immune cells against cancer.

In recent years, CAR-T therapy has received significantly more attention in cancer treatment. With this blogpost we want to present the newest developments of research in this incredibly fascinating fight against cancer.

1. FDA approves new CAR-T therapy for multiple Myeloma

Multiple myeloma is a type of cancer that occurs when abnormal white blood cells build up and form tumours in the bones and other locations. Although there are many treatment options for multiple myeloma, relapse rates are incredibly high and currently available treatments come with a variety of side effects.

Just recently the Food and Drug Administration (FDA) approved Abecma (idecabtagene vicleucel, or ide-cel), for patients with relapsed or nonresponsive multiple myeloma who have tried at four previous lines of therapy. While there is no cure for multiple myeloma, this approval provides a new treatment option for patients who have this uncommon type of cancer.

Abecma is a “living drug” that reprograms a patient’s own T cells to fight cancer. It is the first FDA-approved CAR-T therapy for multiple myeloma.

Several medications, generally in different combinations, are used to treat multiple myeloma. These frequently result in remission, but the treatments can fail, and relapse is common. Abecma is approved for patients who have tried four or more prior lines of treatment, including an immunomodulator like Revlimid (lenalidomide), a proteasome inhibitor like Kyprolis (carfilzomib) or Velcade (bortezomib), and a monoclonal antibody CD38 inhibitor like Darzalex (daratumumab). Patients who have undergone all three drug classes (known as triple-class exposed) are unlikely to respond to additional treatment attempts and have a dismal prognosis.

Results from a previous study showed that nearly all patients treated with Abecma experienced myeloma remission, with a response duration of nearly a year. These results laid the groundwork for the larger Phase II trial to support FDA approval.

This study enrolled 127 patients with relapsed or refractory multiple myeloma who had had at least three prior lines of therapy, including an immunomodulator, a proteasome inhibitor, and a CD38 inhibitor; nearly all had received self-donated stem cell transplants. They had conditioning chemotherapy before receiving a single infusion of Abecma to kill off existing immune cells and make room for new ones.

The total response rate, defined as complete or partial remission, was 72%, with 28% achieving a rigorous complete response. The average response time was 30 days. The median response time was 11 months for all respondents and 19 months for those who provided a complete response. Two-thirds of the 28 patients in the latter group experienced remission lasting at least a year.

Although incredibly promising, CAR-T therapy can cause serious side effects. Unleashing genetically modified T cells can trigger a potentially life-threatening immune reaction known as cytokine release syndrome (CRS), which can lead to fever and chills, falling blood pressure, organ failure and neurologic toxicity. Abecma will be custom produced for each patient and available at certified centers where staff have been trained to manage CRS and neurologic toxicities.

With the approval of Abecma has now become possible to offer patients a new, effective personalized treatment option that is delivered through a single infusion.

2.New CAR T-cell therapy that targets specific growth factor receptors in glioblastoma to eliminate brain tumors

The recent decade has changed the field of cancer research; previously fatal blood malignancies now have therapy choices. Glioblastoma, on the other hand, remains a dangerous mystery.

With the ever-evolving field of immunotherapy, research is being conducted in one of the most aggressive forms of cancer: Glioblastoma.Research has reported that a novel CAR T cell eliminates human glioblastoma cells transplanted into the brains of mice.

In this study, receptors were genetically engineered to recognize the tumour target.

In this case, a protein that is exquisitely tumour specific is being targeted. The critical need is to have a very specific target in the brain that only take out the diseased cells, but keeps the healthy cells unharmed. Within this study a highly specific molecular approach was used: a human retained affinity screen- to make a single chain antibody and reconfigure it as a CAR.

GCT02, the resultant CAR, was long-lasting and had a high affinity for the epidermal growth factor receptor mutant variation III (EGFRvIII) observed on brain tumour cells.

A significant challenge that presented itself was that not all tumour express EGFRvII. This means that some of the tumour cells could be left behind to grow even after treatment. One result of the study yielded the knowledge that going after one protein target in a brain tumour will not be sufficient. It is necessary to use combination therapies and target multiple proteins and multiple antigens at ones. The heterogeneous nature of dangerous tumours like glioblastoma makes them incredibly difficult to treat.

Therefore, the location of cancer is crucial for treatment, especially in the brain, where complete surgical resection is practically difficult. A brain cancer like glioblastoma grows in a very infiltrative manner, similar to the roots of trees.

Studies such as this, have hope for the future of glioblastoma treatment.

3.Fecal Transplants- can it improve response to immunotherapy?

In individuals with melanoma and other malignancies, altering gut bacteria may help overcome resistance to checkpoint inhibitors.

A recent study has demonstrated that patients with advanced melanoma who have not responded to immune checkpoint inhibitor therapy can be converted to immunotherapy responders by receiving a fecal microbiota transplant (FMT) from patients who have responded very well to immunotherapy.

A rising amount of research indicates that the gut microbiome, or the ecology of bacteria and other microorganisms in the intestines, plays an important role in health and disease, including immunological response. Some beneficial microbes produce metabolic by-products that boost immune cell function and reduce inflammation, whereas bad bacteria can cause a leaky gut and an inflammatory response.

Previous research has shown that advanced melanoma patients with more diverse gut bacteria responded better to PD-1 checkpoint inhibitors, such as Keytruda (pembrolizumab) and Opdivo (nivolumab). Patients with a healthy gut microbiome had more active T cells in their malignancies and lived longer without progression. Similar associations have been shown in individuals with bladder, lung, kidney, and liver cancer, as well as in mice with pancreatic cancer.

Such results demonstrated that modifying the gut microbiome could improve treatment responsiveness.

One method of altering the gut microbiome is to provide fecal microbiota transplants (FMT) via "poop capsules" or enemas containing intestinal bacteria from healthy donors or cancer patients who respond well to treatment. Early research found that mice given fecal transplants from cancer patients who responded well had higher T-cell activation and slower tumour progression. This established the stage for putting this strategy to the test in humans.

A first report described results from a Phase II trial that included 16 advanced melanoma patients who initially did not respond to Keytruda or Opdivo used alone or in combination with other therapies.

The patients received a single stool transplant by colonoscopy from donors who reacted well to checkpoint inhibitor treatment and were then put on Keytruda, some for the second time. Six of the fifteen evaluable patients had tumour reduction or stable disease. One person was still responding more than two years later, while four others had been on treatment for over a year with no further disease progression.

Gut bacteria composition quickly moved toward more favorable types associated with checkpoint inhibitor response, T-cell activation, and a reduction in myeloid cells and cytokines linked to immune cell suppression and immunotherapy resistance in these responders. Unless the microbiome was disrupted, such as by the use of antibiotics, these alterations persisted.

The researchers concluded that fecal transplants changed the gut microbiota and reconfigured the tumor microenvironment to overcome resistance to PD-1 checkpoint inhibitors in a subset of persons with advanced melanoma.

Treatment responders reported a rise in some broad families of bacteria and a reduction in others, but the researchers have yet to identify specific beneficial species. It is known that the composition of the intestinal microbiome gut bacteria can change the likelihood of responding to immunotherapy.

The question that remains is what is good bacteria? There are about 100 trillion gut bacteria and 200 times more bacterial genes in an individual’s microbiome than in all their cells put together.

A second study evaluated findings from a smaller Phase I trial including 10 persons with metastatic melanoma who did not respond to PD-1 checkpoint inhibitors. Fecal microbiota transplantation resulted in improved immune cell populations and gene expression in both the gut lining and the tumor microenvironment. Two patients had partial responses and one had complete remission after receiving transplants and commencing immunotherapy.

Based on these impressive results there will be an expansion of the melanoma trial with a larger study of fecal transplants for people with kidney, lung and other types of cancer.

It is expected that the future studies will identify which groups of bacteria in the gut are capable of converting patients who do not respond to immunotherapy drugs into patients who do respond.

This incredibly exiting research raises hope for microbiome-based therapies of cancer.

Considering all these new developments it is safe to say that we've entered a new era of personalized medicine. This is the incredibly exciting future: to treat patients with a very personalized and targeted approach.