CAR T Therapy: From Cancer To Autoimmune Disease, The Lupus Example

This is a series on the advances in CAR T, a remarkable immunotherapy treatment dubbed a “living drug.” This new therapy genetically modifies a patient’s cells to fight cancer, but current research efforts hope to treat autoimmune diseases, organ damage and more. Here we draw attention to promising findings for CAR T lupus treatment. The foundations of CAR T and applications for B cell cancers and multiple myeloma can be found in earlier works in the series.

The previous installments in this series have focused on CAR T therapy as a cancer treatment. A recent study published in the journal Nature Medicine highlights the potential of CAR T therapy beyond this realm—specifically for lupus and other autoimmune diseases.

What is Lupus?

Lupus (systemic lupus erythematosus) is an autoimmune disease that affects women approximately ten more than men, and is characterized by the overproduction of antibodies that attack the body’s own tissues. Lupus symptoms—ranging from mild to life-threatening—often come and go, making the condition hard to diagnose. Characteristic signs such as fatigue, muscle pains, joint pains and fever also coincide with symptoms of other diseases.

FIGURE 1: Lupus symptoms and complications VECTORMINE Link Added

Current Lupus Treatments  

Although lupus has no cure, modern day symptomatic treatments ensure a normal life expectancy for 80-90% of people with lupus. One of our successes at Human Genome Sciences, a company I founded and served as Chair and CEO, was the use of genomics to discover and bring to market the first drug to treat lupus: Benlysta. Although the medicine proved to be effective, for some with lupus even the strongest drugs offer no relief.

CAR T Therapy for Lupus 

In their study, Mackensen et al. test the effectiveness of CAR T therapy for treatment-resistant forms of lupus. The theory derives itself from CAR T cells’ ability to kill cells. In lupus, B cells produce antibodies that attack the body and trigger inflammation (Figure 2). Using CAR T therapy, the researchers aimed to purge the B cell lineage, allowing the body to restore B cells de novo.

To do this, the researchers first collected patients’ white blood cells. The patients then underwent lymphodepletion, the use of chemotherapy drugs (i.e. fludarabine and cyclophosphamide) to preferentially kill B cells. As seen in Figure 3, this drug regimen leaves room for the later infusion of engineered T cells, but can be very dangerous if the immune system is too thoroughly depleted.

FIGURE 2: (A) Anti-CD19 CAR T cells target CD19 often found on naive B cells and plasmablasts. (B) Lysing these B cells prevents the production of autoantibodies—specifically anti-DNA antibodies and anti-RNA binding protein antibodies—that are major drivers in lupus inflammation. Note that long-lived plasma cells without CD19 would not be detected and can continue autoantibody production. MACKENSEN ET AL
FIGURE 3: The CAR T cell process involves extracting T cells from the body, synthetically adding a receptor that detects and binds to antigen CD19, and then infusing the manufactured cells back into the body after preparatory chemotherapy. SEC
Link Added

The team altered the patient T cells with new genetic information. The new, chimeric T cell products contained a new receptor—a single-chain variable (scFv) fragment poised to detect CD19-expressing cells—a 4-1BB costimulatory domain and a CD3 intracellular domain. Figure 4 illustrates these cellular components. The antibody-derived receptor and additional costimulatory structure do not naturally occur on T cells, lending the chimeric nature the therapy is coined after (Chimeric Antigen Receptor T cells).

FIGURE 4: A second generation Chimeric Antigen Receptor T cell combines the signaling machinery of a T cell with an antibody-derived receptor. S. E. LINDNER ET AL. Link Added

Results 

Five patients with severe, treatment-resistant lupus (four women and one man) participated in the study. Lupus impacted several of their organs, including the kidney, heart, lungs, and joints. In addition, these patients did not respond to steroids, antimalarial drugs and other immunosuppressive medicines.

Each of the patients received a transfusion of modified T cells after chemoablation treatment. The chemoablation successfully depleted patient B cells while T cell numbers remained within normal range. Moreover, the team could no longer detect malignant autoantibodies (ie. anti-double stranded DNA antibodies). The participants’ responses to vaccines also remained largely unchanged, suggesting that the CAR T therapy correctly targeted detreminal B cells without damaging the entirety of the immune system.

Three months later, prior symptoms including kidney inflammation, arthritis, fatigue, and heart fibrosis disappeared, and all other immunosuppressive drugs could be discontinued. The symptoms did not return even when B cells began to reconstitute months later. Remission was defined by DORIS, a standardized criteria used to measure lupus symptom severity.

Future Possibilities for CAR T 

This study demonstrates how CAR T can send treatment-refractory lupus to remission. This is a first hopeful step. The search is now on for ways to improve CAR T induced remission for prior B cell ablation using a cocktail of cytotoxic drugs. The study also opens the door to the possibility of applying CAR T to other difficult to treat autoimmune diseases.

PATIENT ADVISORY

Medika Life has provided this material for your information. It is not intended to substitute for the medical expertise and advice of your health care provider(s). We encourage you to discuss any decisions about treatment or care with your health care provider. The mention of any product, service, or therapy is not an endorsement by Medika Life

Editors ChoiceCAR T Therapy: From Cancer To Autoimmune Disease, The Lupus Example
William Haseltine, PhDhttps://www.williamhaseltine.com/
William Haseltine, Ph.D. is chair and president of the think tank ACCESS Health International, a former Harvard Medical School and School of Public Health professor, and founder of the university’s cancer and HIV/AIDS research departments. He is also the founder of more than a dozen biotechnology companies, including Human Genome
More from this author

RELATED ARTICLES

RECENTLY PUBLISHED