CAR-T Cell Cancer Immunotherapy

Each year, the American Society of Clinical Oncology (ASCO) releases its Clinical Cancer Advances report. This in-depth report is published in ASCO’s Journal of Clinical Oncology and covers the major advances made in cancer care over the past year, including prevention, treatment, patient care, and a look toward the future. Each year, leaders in the oncology field also select a single area of research that achieved the greatest progress.

“Clinical Cancer Advances 2018 highlights the most impactful research advances and policy developments of the past year and previews where cancer science is headed. The report was developed under the direction a 20-person editorial board of experts in different oncology subspecialties, as well as cancer prevention, quality of care, health disparities, and tumor biology”. (Source)

For the past 2 years, the Advance of the Year was immunotherapy. Four years ago, ASCO had introduced immunotherapy. (See the Institute’s coverage on this).

This important shift away from cytotoxic therapies has transformed care for many patients. In fact, ASCO estimates that immune checkpoint inhibitors could save 250,000 years of life for U.S. patients with advanced lung cancer for whom a checkpoint inhibitor could be prescribed. Immune checkpoint inhibitors are medicines that release the “brakes” on the body’s immune system, unleashing it to fight cancer.

The 2018 Advance of the Year is a new kind of genetically-structured immunotherapy known as chimeric antigen receptor (CAR) T-cell therapy.

When the immune system is functioning normally, immune cells move around the body looking for things that don’t belong, like bacteria and viruses. These immune cells search for invaders using “receptors,” which can be thought of as antennae or feelers that actually hear signals and reacts accordingly. When receptors find invaders in the body, special immune cells come in to destroy them. These special cells are called cytotoxic T cells. Macrophages can also poison and destroy cancer cells.

In the face of the host’s defense system, cancer cells can counter and hide from immune cells, including, but not limited with nagalese secretions (Source).

When it succeeds to bypass tumor suppressor proteins, the macrophages, dendritic and T cells, cancer cells proliferate and eventually take over the entire host. (Source)

To attempt to ward off this above-mentioned eventuality, cancer immunotherapy has been developed by leading scientists, two of whom have received the 2018 Nobel prize for their research in this realm. (Source)

In this field, immunotherapy is a treatment intended to make the body’s immune system more sensitive to detect and destroy cancer cells. Immune checkpoint inhibitors, have been a relatively successful immunotherapy approach for a few cancers because it pushes the immune system to be more sensitive in its recognition of cancer cells as foreign proteins.

CAR T-cell therapy, however, is somewhat different. It is a type of immunotherapy called “adoptive cell immunotherapy.” As ASCO President Bruce E. Johnson, MD, FASCO, describes it, this technique “allows clinicians to genetically reprogram patients’ own immune cells to find and attack cancer cells throughout the body.”

In CAR T-cell therapy, a person’s T cells are removed and taken to a laboratory. The T cells are genetically changed so they will attack cancer cells. These CAR T cells are grown in large numbers and then injected into the patient. One of the remarkable things about this treatment is that it is a “living therapy.” CAR T cells typically have to be injected only once, because they go on to multiply in the body. CAR T cells continue fighting the cancer in the patient’s body, and their effectiveness may even grow over time.

CAR T-cell therapy successes

Below, three recent examples of the potential that adoptive cell immunotherapy brings to cancer treatment.

Childhood acute lymphoblastic leukemia (ALL). Nearly 3 of every 4 children with leukemia are diagnosed with a type called ALL. Treatment for this form of leukemia has improved  over the years, so 90% of children are still alive 5 years after their diagnosis. But in about 600 children and young adults with ALL in the United States every year, treatment doesn’t stop the disease from returning. Furthermore, after the 5 years mark, these children can develop other cancers and complications. (Source).

In a clinical trial with children and young adults with ALL that had not been stopped by standard treatment, a CAR T-cell therapy called tisagenlecleucel (Kymriah) sent the cancer into remission in 52 of the 63 patients. In 3 out of every 4 patients, the ALL still had not come back after 6 months. Based on the results of this study, in August 2017, the U.S. Food and Drug Administration (FDA) approved tisagenlecleucel to treat children and young adults with recurrent ALL.

Non-Hodgkin lymphoma. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and is quite aggressive. Many people can be successfully treated with a combination of chemotherapy and rituximab (Rituxan), a targeted therapy. However, these types of lymphomas can sometimes worsen during treatment, called “refractory lymphoma,” or they can come back after treatment, called “recurrent lymphoma.” In these cases, CAR T cells may be an effective treatment option.

A clinical trial used tisagenlecleucel to treat people with DLBCL that had worsened after at least 2 previous treatments. The lymphoma went into remission in 43% of the patients in the study. At 6 months after receiving the CAR T-cell therapy, the lymphoma had still not come back in nearly 80% of the patients.

Another study used a different CAR T-cell therapy to treat refractory lymphoma or recurrent lymphoma. In this study, people had DLBCL, primary mediastinal large B-cell lymphoma (an aggressive form of DLBCL that forms in the chest), or transformed follicular lymphoma (a slow-growing subtype of NHL that has turned into DLBCL). The CAR T-cell therapy in this study was called axicabtagene ciloleucel (Yescarta). The immunotherapy slowed or stopped cancer growth in 82% of the patients, and the cancer completely disappeared in more than half (54%). After nearly 9 months, about 40% of the patients still had no signs of cancer. In October 2017, the FDA approved axicabtagene ciloleucel for the treatment of DLBCL that has not been stopped by 2 or more previous treatments.

Multiple myeloma. Multiple myeloma is a blood cancer that involves the plasma cells in the bone marrow. Plasma cells play an important role in the body’s immune system. Multiple myeloma is an incurable disease with conventional oncology, and only about one-half of people live 5 years after a diagnosis.

Results from an early clinical trial presented at the 2017 ASCO Annual Meeting showed that a type of CAR T-cell therapy that targets a biomarker known as B-cell maturation antigen (BCMA) can stop multiple myeloma in its tracks. This study included 35 people with multiple myeloma that had come back after treatment, called relapsed or recurrent, or was resistant to treatment, called refractory. Of those 35, 33 patients (94%) had their multiple myeloma go into remission within 2 months of receiving the BCMA CAR T cells. Gene therapy was also successful for a pancreatic cancer patient. (Source)

CAR T-cell therapy’s limitations and risks

This new cancer immunotherapy treatment approach does come with serious risks that need to be considered before starting therapy. In particular, possible side effects include cytokine release syndrome (CRS), neurologic problems and auto-immune reactions.

CRS is caused when CAR T cells produce a storm of inflammatory molecules. CRS can cause a long-lasting fever, low blood pressure, difficulty breathing, and problems with different organs. Severe CRS can be a life-threatening problem that requires intensive medical care, including the use of a ventilator, drugs to increase blood pressure, and seizure medicines. In August 2017, the FDA approved tocilizumab (Actemra) to treat CRS.

CAR T-cell therapy can also cause neurologic problems. These may include problems remembering words, difficulty speaking, being less alert, delirium, hallucinations, seizures, and coma. In many patients, these problems eventually go away on their own, but patients have died from these problems.

In people with ALL, there were many serious side effects from the CAR T-cell therapy. Nearly half of the patients developed severe CRS. Another 15% of patients had neurologic problems.

For non-Hodgkin lymphoma treatments, serious side effects were seen in the study participants. Around 1 in 4 patients taking tisagenlecleucel experienced severe CRS, and around 1 in 10 had neurological problems. Axicabtagene ciloleucel caused severe CRS in around 1 out of every 10 patients, and nearly 3 out of every 10 had neurological problems.

On the other hand, among the patients treated for multiple myeloma, only 2 patients experienced severe CRS, and none experienced neurologic complications from BCMA CAR T-cell therapy.

To read ASCO’s full 2018 Clinical Cancer Advances report (available as a PDF; 56 pages), visit ASCO’s website at www.asco.org/cca.

Chimeric antigen receptor (CAR)-T cells in multiple myeloma.

The last decade has witnessed transformative changes in multiple myeloma treatment, with a shift away from chemotherapy-based treatment and stem cell transplants and toward an array of biological therapies. However, most patients eventually died. With immunotherapy, where the body’s own healing powers  (its immune system) is activated, there is hope for better results.

Cancer cells are immunologically similar to normal ones and can evolve mechanisms to evade immune surveillance. In contrast, in CAR therapy, genetic engineering generates a customized T cell that recognizes a distinct protein on cancer cells, bypassing the need for the immune system to take its usual multitude of steps to fight cancer. Also, these immune cells can stay in circulation for years, ready to recognize and attack dormant cancer cells that may re-emerge over time. (See other blog).

Conclusion

While it is still too early to characterize genetically-engineered cancer immunotherapy as a general cure of cancers, this approach is going in the right direction. However, given significant side effects for a significant number of cancer patients, it may be wise to first put in place holistic techniques that also target the immune system. (Source)

If these were not successful, then CAR-T’s genetically-engineered approach would be useful in that this technology would help to prevent patients from getting harmed by cytotoxic chemotherapy and radiation while getting their immune system to be more sensitive in the recognition and fight against cancer cells, albeit with a risk of immune over-action against other tissues.

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