Fighting Fire with Fire

Rheumatologist Maximilian Konig is leading the charge at Johns Hopkins to develop and deliver immune effector cell therapies to achieve long-term remission, and even a functional cure, for patients with severe rheumatic diseases ranging from lupus to antiphospholipid syndrome (APS).

Maximilian Konig looks at his research on a computer screen

Maximilian Konig is guiding the launch of the Johns Hopkins Cellular Therapy Program for Autoimmunity.

Published in Clinical Connection - Winter 2024 - 2025

There is a revolution brewing for patients with severe autoimmune diseases — a revolution that promises to be nothing short of “transformative,” asserts Maximilian Konig, M.D., assistant professor of medicine.

Konig is leading the charge at Johns Hopkins to develop and deliver immune effector cell therapies — borrowing from strategies that have become the standard of care in treating blood cancers — to achieve long-term remission, and even a functional cure, for patients with severe rheumatic diseases ranging from lupus to myositis to antiphospholipid syndrome (APS).

Konig is guiding the launch of the Johns Hopkins Cellular Therapy Program for Autoimmunity, which is expected to enroll its first patients in clinical trials in 2025. Housed within Rheumatology and Medicine, the program is believed to be the first in the United States that is operated independently of an oncology unit.

“We have created a dedicated infrastructure for a program that specializes in treating patients who have autoimmune and rheumatic diseases using engineered T-cell therapies and bispecific antibody approaches,” Konig says. “We hope this program will serve as a model for a future where rheumatologists are empowered to take care of these patients and become proficient in managing the unique side effects of cell therapies.”

Unlike existing treatments for rheumatic diseases, which may bring debilitating — even deadly — side effects because they leave the patient at long-term risk of infection, immunotherapies like the ones being offered in the new Johns Hopkins Cellular Therapy Program work by harnessing the body’s own immune cells to identify and vanquish dangerous cells that cause autoimmune tissue damage, through a one-time procedure.

“Consider a 30-year-old woman with severe lupus whose disease is hard to control and prognosis poor: She might die from infection, complications of renal failure and dialysis, or other organ damage from uncontrolled lupus,” says Konig. “Through cell therapy, we have a chance to ‘reset’ this patient’s immune system to the extent that, for all intents and purposes, you can’t tell she had lupus. Her symptoms may disappear and — if all goes well — she no longer needs to be on medication.”

These cell therapies, he says, “are transformative in their potential.”

Eliminating Enemies Within

Chimeric antigen receptor (CAR)-T cells are a type of “living drug” immunotherapy that has been successfully used to treat patients with B cell-driven blood cancers. But now the same therapy is being applied to patients with severe rheumatic diseases: The approach depletes B cells with remarkable results, achieving drug-free disease remission in many patients.

B cells are a type of white blood cell that makes infection-fighting proteins called antibodies. In rheumatic disease, some “bad actor” B cells emerge; in effect, they “go rogue,” attacking the body’s own tissues and causing the damage we associate with a given autoimmune disease.

“Over the last several years, a whole new area has emerged in how we can treat autoimmune diseases,” Konig explains. “If we can deeply deplete the patient’s B cells, we can force the body to reconstitute its missing B cell pool. When that happens, we see untrained [naïve] B cells emerge that no longer recognize self-proteins as foreign — the bad actors are gone. In effect, the patient’s immune system is forced to forget that it had previously started to attack the body.”

The treated patient’s previously active and potentially life-threatening autoimmune disease can completely disappear, he says. Engineering and equipping the body’s own “killer” T cells, through expression of a CAR, to rid the patient’s body of these bad B cells is key to this success.

So just what can patients with rheumatic diseases expect when they begin treatment within the new Johns Hopkins Cellular Therapy Program for Autoimmunity?

CAR-T cells are currently given as part of clinical trials, Konig explains, and details differ between types of therapy and specific protocols. Patients generally begin by first providing their white blood cells (containing the T cells) in a process known as apheresis, a prerequisite for all “autologous” (patient-derived) cell therapies. The collected cells are then shipped to a specialized lab to be engineered, he says.

During the days to weeks the patient’s T cells are being engineered to make CAR-T cells, the patient undergoes a course of conditioning therapy (called lymphodepletion therapy) to reduce their immune cell numbers and provide the right environment for the CAR-T cells to engraft. Then, the patient returns to Johns Hopkins to have the newly engineered CAR-T cells infused. Patients who receive CAR-T cells are closely monitored in the hospital over the next seven to 14 days by Konig and other clinicians. Then they return home but continue to be monitored closely to pick up on any potential complications (typically related to the very active T cells).

“We hope this program will serve as a model for a future where rheumatologists are empowered to take care of these patients and become proficient in managing the unique side effects of cell therapies.”

Maximilian Konig
Portrait of Maximilian Konig

While autologous CAR-T cell therapies require patients to provide their own blood cells to be engineered, Konig says that many researchers see a bright future in “allogenic” approaches: Using healthy donor cells that are engineered in bulk and can be banked. The idea here is that a healthy donor donates cells that are specifically modified (requiring some additional engineered steps to disarm them and avoid immediate rejection when infused into another human) and then frozen. When needed for a patient with rheumatic disease, these cells could be “pulled off the shelf,” thawed, and then infused.

In contrast to the individual manufacturing with autologous cell therapies, banked cell products are premanufactured from a healthy donor’s T cells, which may enable more predictable behavior across patients. The result: streamlined manufacturing, reduced costs and faster treatment for patients. Konig, including his own lab, is a strong proponent of this approach, and an ongoing CAR-T cell therapy trial (GLEAM) for patients with severe lupus and ANCA-associated vasculitis offered at Johns Hopkins uses such allogenic CAR-T cells.

In addition to providing T-cell therapies that require cell engineering, the Johns Hopkins program will offer an alternative strategy using bispecific T cell-engaging antibodies (“bispecific antibodies”). These can target and latch onto two different target molecules, and thereby engage and redirect the patient’s own T cells to bind and kill B cells. The end effect is an off-the-shelf therapy that shows comparable potency to CAR-T cells without requiring any apheresis, cell engineering or conditioning therapy. Bispecific antibodies are similarly infused (typically multiple times) and require an inpatient stay and close follow-up monitoring since they show similar side effects to CAR-T cells, Konig explains.

While using cellular therapies to treat autoimmune diseases is still in its early days, the results so far have been encouraging, Konig says: “These therapies have created much excitement. Many patients are emerging from this one-time treatment with no signs of disease. It is too early to say they are ‘cured,’ but if we can allow patients to live drug free, accruing no further damage to their organs for five, 10, or 15 years, we have already won.”

A New Model

As the number of patients eligible for these off-the-shelf therapies is expected to grow rapidly in rheumatology in the next years, the team at Johns Hopkins is looking to rheumatologists to meet the need. “The program we have created, and are continuing to build, is putting us ahead of the curve,” Konig says. “We’re opening pathways for the large population of our patients to receive these kinds of transformative treatments.”

Key to the new cellular therapy program is an experienced and closely knit team, including senior research nurse Liana Boccio, who brings deep experience in using CAR-T cell treatment from oncology to rheumatology; Gwendolyn Leatherman, a research nurse manager with extensive experience in clinical trials; and physicians in hospital medicine, Margueritta El Asmar and Michael Cammarata. The program also capitalizes on the expertise of staff members in the clinical trial units, colleagues in oncology, and the deep expertise of the Division of Rheumatology’s Centers of Excellence.

The new Cellular Therapy Program at Johns Hopkins, Konig believes, “can be an innovative model to show hospitals across the country that cellular therapies can be made widely available to patients with autoimmune diseases by putting them in the hands of rheumatologists.” 

On the Horizon: Precision Immunotherapies

Even as Maximilian Konig and his team build out the new Cellular Therapy Program at Johns Hopkins, he and researchers in his lab are hard at work in their quest to shape the future of immunotherapy for rheumatic diseases. The goal: controlling disease without increasing the risk of infection. 

Only a very small percentage of B cells in patients with a rheumatic disease are “bad actors” and cause tissue damage. Getting rid of just this small number of rogue B cells could get patients into remission or even cure. “Our current approaches, whether CAR-T cell therapy or monoclonal antibodies, however, take a ‘sledgehammer’ approach, depleting all of the patient’s B cells to get rid of the few rogue disease drivers — and it works,” he says. “But this brute force approach comes at the cost of the patient losing the ability to fight infection effectively.”

In his lab, Konig’s research team and collaborators are working to develop precision immunotherapies that selectively target and eliminate the rogue cells, leaving the 95–99% of the patient’s immune system that protects from infection and cancer intact. By combining the potency of current immune effector cell therapies with therapeutic precision, says Konig, “we hope we will be able to achieve lasting disease remission with minimal risk to patients.”

At the 2024 American College of Rheumatology Convergence meeting, his group unveiled four precision immunotherapy approaches that were developed at Johns Hopkins that have the potential — through further development — to become the first tailored therapies for patients with lupus, antiphospholipid syndrome, ankylosing spondylitis and celiac disease, Konig says.

Capitalizing on his lab’s findings in preclinical models and blood samples donated by rheumatic disease patients seen at Johns Hopkins, the team has begun collaborating with Baltimore-based accelerator Blackbird Laboratories to move some of these precision-based strategies forward. The goal, Konig says, is to begin clinical trials in humans within five years.

Looking ahead, Konig says, “There’s a lot of hope. And a lot of work to be done.”

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