Immunology & Inflammation | Commercial Potential & Clinical Frontiers

Session Focus

Gravallese framed the field’s position. Immunology has produced some of the most successful medicines of the past decade, with tremendous progress in autoimmune disease and allergy. The field is now evolving toward CAR-T and T cell engagers, raising the possibility of moving beyond chronic immune suppression toward deeper and more durable control.

The session examined what that would mean for patients, how efficacy balances against safety, and where the next major opportunities sit. Mortensen joined after the session began, having had a flat tire en route.

Beyond Inhibiting Inflammation

Alyssa Johnsen MD, PhD, trained as a rheumatologist and immunologist, described the field’s history as being about inhibiting inflammation and primarily cytokines, which it has become quite good at.

She was clear that this should continue, because the field keeps learning that particular pathways drive particular diseases, citing IL-23 in psoriasis and TL1A in inflammatory bowel disease as examples.

Her point was that cytokine inhibition alone will probably not achieve the levels of remission the field wants. Reset through cellular depletion has taken it part of the way. The open question is what happens after the immune system is reset: whether natural recovery suffices for all patients, or whether mechanisms such as tolerance need to be engaged deliberately. She noted emerging data on establishing tolerance.

Scott Requadt framed the shift as moving from immunosuppression toward a longer, more durable potential cure. The distinction people draw is between immune dimming and immune reset.

The patient case is what makes this urgent. The standard of care for autoimmune patients is chronic lifelong therapy with consequences that follow from that. A shorter duration of therapy leaving a patient free of treatment for a period, or indefinitely, would be an enormous improvement.

What Immune Reset Actually Requires

Asked what would demonstrate a genuine reset rather than a deeper response, Requadt’s first answer was that the ultimate test is time, though hypotheses exist about the necessary foundation.

The emerging explanation for why CD20 antibodies plateau is instructive. They deplete B cells in the blood but typically do not reach pathogenic B cells resident in conserved tissue niches, including lymphoid and fibrotic tissue. Those surviving clones sow the seed for relapse.

That is why traditional CD20 and CD19 monoclonal antibodies require maintaining chronic B cell aplasia. As B cells return, relapse follows, because depletion was never complete.

The hypothesis CAR-T has demonstrated in principle, and T cell engagers are attempting to follow, is whether pathogenic B cells can be fully depleted including in hard-to-reach niches, and whether maintaining that depletion allows B cells to regenerate with a more naive phenotype.

That is assessable. Examining the recovering B cell pool, a high proportion of memory B cells would be a poor sign, while predominantly naive and immature cells would be promising. B cell receptor sequences can be compared before and after treatment to test clonal similarity.

Requadt reported recent data in lupus patients consistent with the CAR-T findings, with durable full remissions out to a year in some patients. His honest caveat: you probably do not know whether you have achieved reset until patients have been followed for multiple years, and he wished there were a better measure.

Johnsen added a concern about etiology. Patients who develop these diseases carry genetic predisposition, and some environmental trigger starts the process. Even in patients meeting the definition of complete depletion, she wonders whether a clock is ticking toward recurrence. That is why she is interested in what else can keep patients in remission, whether natural recovery of the immune system suffices, or whether tolerizing approaches or dampening the original predisposing triggers will be required.

Which Antibodies Actually Matter

Gravallese raised a striking observation from the CAR-T literature: pathogenic autoantibodies largely disappear following B cell depletion while long-lived plasma cells continue producing the antibodies needed for vaccine response. She asked whether that is genuinely the case or whether the field has not looked deeply enough.

Requadt’s answer turned on a distinction. Not all autoantibodies are pathogenic. Some correlate with disease and some are genuinely causative, which means eliminating all of them with a sledgehammer is unnecessary.

Variability between patients compounds this. The field discusses broad disease categories, but within any category patients present across a spectrum, which makes a one-size-fits-all approach unlikely to work. The realistic goal is working well in a significant number of patients.

His company’s approach is to select diseases where autoantibodies either are not pathogenic, or where they are secreted by short-lived plasma cells and plasmablasts rather than long-lived plasma cells. A CD20 T cell engager can fully deplete the former. Long-lived plasma cells are preserved by design, because they carry humoral immunity and vaccine protection.

The obstacle is diagnostic. No gold standard exists allowing a rheumatologist to determine which approach a given patient needs, so the field remains in an empirical treatment paradigm.

His strategic conclusion follows from that. The most important thing is developing a treatment rheumatologists feel comfortable administering fairly early in the disease course, with the hope of inducing dimming or reset in some proportion of patients. Where pathogenic autoantibodies come from the earlier plasma compartment, that works. Where it does not, clinicians move to therapies depleting long-lived plasma cells through targets such as BCMA.

He expects progression rather than competition. Where the field discusses CD20, CD19 and BCMA T cell engagers as competing targets, he sees potential complementarity, with rheumatologists sequencing them.

Choosing and Combining Targets

Johnsen noted the field does not yet fully understand which diseases are best matched to which targets, and returned to heterogeneity within a diagnosis. Any treating rheumatologist knows lupus is not one thing, so patients within a single disease may respond better to different targets.

She described the field rewriting its own textbooks. The classical picture had specific markers expressed at defined stages of B cell development, which suggested that autoantibody-driven disease required eliminating long-lived plasma cells while B cell-driven disease pointed toward CD19 or CD20.

Empirically that is proving unreliable. Some BCMA-targeted agents deplete considerably earlier in the B cell life cycle than expected, and CD19 and CD20 agents are removing antibody-producing cells.

The ideal would be individualizing target selection by a patient’s antibody profile, which the field cannot currently do.

Requadt described examining tri-specific approaches targeting CD19 and CD20, or CD19 and BCMA, and the difficulties encountered with dual-targeting antibodies.

Mortensen, joining after the opening, pushed toward a more tunable version of reset, on the grounds that different autoimmune diseases may require different depths of depletion, different targets and different platforms.

Key Takeaways

1. Cytokine inhibition remains valuable but insufficient for the remission levels the field now wants.

2. CD20 antibodies plateau because tissue-resident pathogenic B cells survive, which is what necessitates chronic aplasia.

3. Naive phenotype on B cell recovery is the readable early signal, alongside clonal comparison before and after treatment.

4. Confirming a genuine reset takes years of follow-up, and no better measure currently exists.

5. Not all autoantibodies are pathogenic, and preserving long-lived plasma cells protects vaccine immunity by design.

6. The field lacks a diagnostic to match patient to target, leaving an empirical paradigm and likely sequential rather than competing therapies.