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.

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.

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).

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.

The post CAR T Therapy: From Cancer To Autoimmune Disease, The Lupus Example appeared first on Medika Life.

CAR T is an effective treatment for some hard to treat cancers. This “living drug” is made by extracting killer T cells from the body, manipulating them to target cancer cells, multiplying the newly engineered cells and infusing them back into the body. Development over the last forty years has evolved the precision, efficiency and safety of this technology. Arguably the best example is the treatment of  B cell cancers.

B cells to B cell cancers

CUSABIO Link Added

Figure 1 illustrates the development of antibody cells. B cell maturation begins with stem cells in the bone marrow and is completed with the antibody producing plasma B cells.

Typically, threats to the body leave trails of foreign antigen which can be followed. B cells detect these antigens and proliferate to eliminate pathogens, but these numbers quickly subside. This is done by design. The body regulates this process to ensure the bloodstream is not flooded with too many antibodies to prevent normal function. However, this system can go awry at any point. B cell precursors, intermediate cells or plasma cells can mutate and grow uncontrollably, causing damage to the body rather than shielding from it. When this happens, the immune system weakens and B cell cancers result.

LYMPHOMA CANADA

B cell lymphomas originate from the lymphatic system organs, vessels and tissues, such as the lymph nodes or the spleen. In contrast, leukemias circulate in the bone marrow and blood instead of the lymph organs. Although multiple myeloma is also a cancer of the bone marrow, it entails the abnormal growth of plasma B cells in particular.

Treating B cell cancers

Chemotherapy and radiation most successfully reduce the size and quantity of B cell tumors. Partial remission is very achievable, but complete remission—the total absence of cancer— is much more difficult to attain. For many, the cancer may temporarily recede for months or years after treatment before recurring. And when the cancer recurs, it can be resistant to treatment.

CAR T cell therapy addresses this problem by transforming patient immune cells into an anti-cancer drug. Cells are taken from the body and modified to detect the tumor cells. CAR T cells are fitted with a fusion protein (scFV, Figure 3) made from antigen-recognizing regions of antibodies. This component is typically engineered to target CD19, a B cell antigen known for its role in B cell signaling. This protein is found in B cells of all stages and is present on the surface of many B cell cancers. CD19 is not found on hematopoietic stem cells—those which have yet to mature and gain purpose; as a result, the therapy is less likely to target non-cancerous immune cells, an ideal quality in a therapeutic target.

FIGURE 3: CD19 is an antigen expressed on cancer cells. CAR T cells are fitted with an antigen recognition domain, a single chain variable fragment (scFV), to target the CD19 on the surface of these cancer cells. Once the antigen domain binds to the cancer cell, the CAR T cell can induce apoptosis to eliminate the tumor cell.

BRITTEN, OLIVER, ET AL. 2019 Link Added

Once the CAR T cell binds to CD19 on the tumor cell, several signals are released from the endodomain that trigger cell death of the tumor cell through apoptosis. The co-stimulatory molecules found in the interior of the CAR T cell allow it to multiply and persist in the body.

Normal T cells from the body lack the precision of this antigen recognizing protein and usually require specific proteins—major histocompatibility complexes—to present the antigen and facilitate similar binding. CAR T cells forgo these steps, producing superior hybrid molecules which combine antibody detection with T cell signal transduction. This synthetic engineering defines the chimeric nature of Chimeric Antigen Receptor T cells.

Why CAR T therapy?

As of publication, CAR T is only considered after standard cancer treatments have run their course. Why, then, do people turn to CAR T therapy if it is only considered after several other lines of treatment?

For those who have B cancers which are unresponsive to alternative anti-cancer treatments, CAR T can deliver lasting remission and extend life expectancy by several years—sometimes without additional treatment.

NOVARTIS

For example, one study revealed that 44% of young patients with acute lymphoblastic leukemia (ALL) live at least five years without relapse after CAR T therapy. This is especially remarkable given how difficult it can be to treat the condition and the less than 10% five-year survival rate. Approved CAR T therapies also exist for patients with diffuse large B cell lymphoma (DLCL), follicular lymphoma, mantle cell lymphoma and multiple myeloma.

ACCELERATING CANCER IMMUNOTHERAPY RESEARCH

There is a caveat—it is possible to experience relapse after CAR T therapy. One contributing factor is CD19 antigen escape, a type of CAR T resistance. As illustrated in Figure 5, patients with antigen escape develop cancer cells which no longer express CD19 and thus escape recognition by CAR T cells. So while CD19 targeting has proven effective, this phenomena highlights the need to find alternative antigen targets to improve the drug’s efficiency.

One possible solution is dual targeting CAR T cells. By engineering T cells which detect more than one antigen on cancer cells, the therapy has a greater chance of attacking tumor-only cells and overcoming antigen escape. Current contenders include dual targeting of antigens CD19 and CD22, as well as CD19 and CD20.

Summary 

CAR T shines best in solving what other therapies cannot. When other lines of cancer treatments such as chemotherapy or radiation cause relapse, CAR T therapy often provides a more lasting remission. There’s promise for these engineered T cells to become even more effective in the future with the advent of dual-targeting CAR T cells. And while none of the six FDA approved CAR T therapies are currently used as first-line treatment, developments are underway to establish this innovative technology as a primary line of defense. This is a major step forward for treating B cell cancers, and we can anticipate more to come.

The post The Remarkable Research Of CAR T Therapy: B Cell Cancers appeared first on Medika Life.