When it comes to treating cancer, we have all heard the terms “chemotherapy” and “radiation therapy” at some point — discussing a close friend’s or family member’s cancer diagnosis, watching a soapy medical TV drama, reading an article about cancer treatments, you name it. Although chemo and radiation therapies are amazing cancer treatments, they have pitfalls.

We are starting to see cancer treatments that are centered on a more natural, targeted approach, rather than using synthetic chemicals and controlled doses of radiation.

One such treatment is immunotherapy, which uses the body’s own immune system to fight cancer.

Three interesting breakthroughs in immunotherapy include CAR-T therapy, PD-L1 inhibitor combination therapy, and ctDNA analysis. These three advances can be thought of, respectively, as individualized soldier cells, a chemotherapy and immunotherapy crossover, and a tool for early cancer detection.

On April 17, 2012, at the Children’s Hospital of Philadelphia, an 8-year-old girl was at a crossroads. Emily Whitehead had struggled for three years with leukemia, a type of cancer resulting from DNA mutations in the bone marrow. Her chemotherapy treatment hadn’t shown promising results, and in a last-ditch effort, Emily’s family accepted a new therapy — CAR-T. Fortunately, Emily’s response was a wild success, showing complete remission after just three weeks, thus making her the first child cured by CAR-T therapy.

Chimeric antigen receptor T cell, or CAR-T cell therapy, is a new immunotherapy recently introduced as a treatment for hematologic cancers, or blood-related cancers, such as leukemia. CAR-T cell therapy uses the patient’s own T cells, a type of white blood cell with a key role in the immune system, to target invasive molecules called antigens and trigger an immune response. In this therapy, T cells are extracted from the patient and modified to produce a synthetic CAR protein that has been engineered to seek out a specific antigen on malignant cells and selectively kill those malignant cells.

Currently, CAR-T cell therapy produces the most successful results for acute lymphoblastic leukemia, as demonstrated through Emily’s miraculous recovery. Clinical trials from as early as 2012 have demonstrated 70-90% of participants reaching complete remission, which the National Cancer Institute defines as the “disappearance of all signs of cancer in response to treatment.” This does not always mean that the patient is free of cancer, but it is an extremely positive response.

Even in its infancy, CAR-T cell therapy is gaining recognition in communities around the country, including in Vermont. Shawn Thompson-Snow, a local retired drug, alcohol and mental health counselor, was diagnosed with Multiple Myeloma (MM), a cancer originating in the bone marrow, in the fall of 2019.

The Addison County resident has maintained an optimistic attitude toward his diagnosis, and the recent FDA approval of CAR-T cell therapy for MM makes him a possible recipient in the future. Although Thompson-Snow has gone through and benefited from more traditional chemotherapy and radiation treatments, he is drawn to the more natural technique of CAR-T cell therapy.

“I like the fact that it’s not, ‘Let’s bomb you with some horrible chemicals … that don’t belong in your body,’” he said. “These are your cells. They’re trained to be little fighters.”

While a few complications of his MM need to be alleviated before he can be approved for the therapy, Thompson-Snow is extremely optimistic that CAR-T cell therapy will be a promising treatment for MM in general.

Infographic by Ruby Warner

ANOTHER NEW THERAPY

When fighting a battle, masses of soldiers are critical in order to overwhelm your enemy. CAR-T therapy creates the soldiers necessary for the battle against cancer, but masses aren’t the only factor that come into play during this fight. A therapy that prevents cancer from employing one of its growth strategies can also give the patient the upper hand.

The following therapy works on a cellular level and is rather technical.

A strategy used by cancerous cells to invade a human body is to hijack the joining of molecules, or ligation, between a protein and its ligand (the binding molecule). The protein is called programmed death-1 (PD-1) and its ligand is called programmed death ligand-1 (PD-L1). PD-1 is located on the surface of T cells. When ligated, PD-1 and its ligand PD-L1 prevent the human immune system from becoming overactive and causing damage, but cancer cells abuse this ligation to lower the body’s defense mechanisms so they can proliferate. Specifically, the cancer cells coat themselves with PD-L1 and ligate to PD-1 on T cells, inactivating the T cells.

PD-L1 inhibitor immunotherapies prevent cancerous cells from using this strategy by stopping PD-L1 from binding to PD-1. Standalone PD-L1 inhibitor therapies have shown positive outcomes in some cases, but in the context of particularly tricky cancers (e.g., pancreatic cancer), they have fallen short. Combination therapies involving a PD-L1 inhibitor in conjunction with chemotherapy have shown promising results in cases where standalone therapies have fallen through.

A 2019 study conducted by researchers from Massachusetts General Hospital, Harvard Medical School and Northeastern University used a PD-L1 inhibitor and gemcitabine, a chemotherapy agent responsible for preventing the division of cancerous cells. The results were very exciting, demonstrating a 90% reduction in tumor volume and greatly increased survival rates in mice receiving the therapy. As encouraging as these results are, some of the experiments demonstrated inconclusive results, prompting the need for further research before researchers can declare this PD-L1 inhibitor combination therapy a viable counter to one of cancer’s potent attacks.

UNDERSTANDING EFFECTIVENESS

As with all battles, victory doesn’t come without its fair share of challenges. Though immunotherapy can be a great benefit to many patients, there is a significant variability in clinical benefit of immunotherapy. Even patients with similarly progressed cancers of the same type may respond differently to the same therapy.

Luckily, recent research has identified a new means to predict clinical outcomes of immunotherapy and personalize treatment — circulating-tumor DNA (ctDNA). ctDNA is a fragment of a molecule released by tumor cells that can then be tracked in the patient. The information coded in ctDNA will hopefully provide doctors with valuable insight regarding a specific patient’s response to treatment. By analyzing ctDNA in patient’s blood samples, researchers can now know the genetic mutations on cancer cells and thus predict clinical outcomes and therapy resistance.

While masses of fighters (T cells) and clever strategies (PD-L1 inhibitors) help win battles, so does reconnaissance (ctDNA tracking). Early cancer detection is especially meaningful because treatment is more effective and success more attainable when the cancer is less complex and invasive. Using ctDNA, doctors can potentially detect cancer at a rather early stage from just a single drop of blood. What’s more, ctDNA from blood samples could be more representative than a tumor biopsy for a disseminated disease that has extended beyond localized tissues and organs.

While ctDNA is excellent at identifying certain types of cancers, such as bladder and breast, further research is needed in order to use ctDNA for detection of other, more obscure, cancers.

Cancer research has been at the forefront of the scientific community for centuries. Technological advances such as CAR-T, PD-L1 therapy, and ctDNA analysis have made it possible to diagnose cancers and treat them with targeted therapies.

The continual discovery of new treatments will give us the upper hand we need in the fight against cancer.

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Learn more

Nobel prize for discovery of PD-L1

nature.com/articles/d41586-018-06751-0

General Information on Immunotherapy

cancer.gov/about-cancer/treatment/types/immunotherapy

Sources

PD-L1 Trial

nature.com/articles/s41598-019-41251-9

Emily’s Story

emilywhiteheadfoundation.org/our-journey

CAR-T cell therapy

doi.org/10.1016/j.bbmt.2016.09.002

ctDNA in early detection

sciencedirect.com/science/article/abs/pii/S0163725819302104?via%3Dihub