How Much Do Modern Cancer Treatments Worsen Autoimmune Disease?

Chimeric antigen receptor (CAR) T-cell therapies pose no special safety issues for cancer patients with comorbid autoimmune diseases, and while so-called checkpoint inhibitors for cancer do come with increased risk for acute rheumatic disease symptoms, they don’t appear to increase risk for chronic conditions very much, two separate studies indicated.

Among cancer patients undergoing CAR T-cell therapy, those “with pre-existing autoimmune or inflammatory disease had similar safety and cancer outcomes after CAR T-cell therapy as those without autoimmune or inflammatory disease,” Jeffrey Sparks, MD, MMSc, of Brigham and Women’s Hospital in Boston, and colleagues reported in Lancet Rheumatology.

Meanwhile, Pushti Khandwala, MBBS, of Jefferson Einstein Philadelphia Hospital, and colleagues found that checkpoint inhibitors raised the odds of developing new-onset rheumatoid arthritis (RA) by 26% (P<0.0001) compared with other types of cancer therapy — but rates of incident lupus and systemic sclerosis were actually lower with the immune modulators, and no difference in risk for other inflammatory autoimmune diseases could be discerned, the group reported in ACR Open Rheumatology. It wasn’t clear why RA alone among these conditions had the increased risk.

These new treatments have revolutionized cancer therapy in recent years by defeating the mechanisms by which tumors evade immune attack. Checkpoint inhibitors do so by preventing tumor cells from flipping a molecular “off switch” on T cells. These switches include the CTLA-4 protein and programmed death ligand (PDL) receptor. Tumor cells may carry proteins that bind those targets, causing T cells that would otherwise kill them to shut down and even die. Specific drugs exploiting these mechanisms include the CTLA-4 targeting agent ipilimumab (Yervoy) and the anti-PDL products nivolumab (Opdivo) and pembrolizumab (Keytruda).

CAR T-cell therapy also seeks to mobilize an immune attack on tumors, in this case by modifying patients’ T cells ex vivo to target specific proteins carried by that patient’s particular malignancy.

Since these agents may affect immune system function, there have been concerns that they might worsen or cause autoimmune diseases.

Outcomes With CAR T-Cell Therapy

With CAR T-cell therapy, cytokine release syndrome (CRS) — an important side effect for most recipients — could theoretically be especially damaging for patients with pre-existing autoimmune conditions. Sparks and colleagues therefore examined records for patients undergoing the therapy at Boston’s Dana-Farber Cancer Institute to see whether safety and outcomes differed for those with versus without autoimmune comorbidities.

A total of 499 patients receiving CAR T-cell therapy for lymphoma were identified, of whom 47 had autoimmune conditions. The most common was psoriasis (19%) followed by Hashimoto’s thyroiditis (11%); all told, more than 30 disorders were represented.

Reassuringly, CRS was neither more common nor more severe in the autoimmune group than in the others (78% vs 83% for all grades; 0% vs 5% for severe CRS). Similarly, rates of a related condition known as immune-effector cell-associated neurotoxicity syndrome also were essentially the same in the two groups (for severe disease, 23% without autoimmune disease vs 19% with). As well, among 106 patients with multiple myeloma receiving a similar therapy involving the B-cell maturation antigen, no hints of worsened safety were seen for the six patients with comorbid autoimmune disease.

Sparks and colleagues also found that lymphoma and myeloma outcomes such as overall and progression-free survival were the same irrespective of autoimmune comorbidities.

And another encouraging finding was that patients’ autoimmune conditions may have improved with the cancer treatment. Flare rates were lower in the year following treatment compared with the year prior, immunosuppressive medication dosages were reduced, and rates of low disease activity and remission increased. This was an intriguing finding, insofar as these immunomodulating therapies weren’t designed or expected to show anti-rheumatic effects, unlike the purpose-made CAR T-cell therapies for autoimmune disease that have recently energized the rheumatology community.

Checkpoint Inhibitor Safety

The major concern with checkpoint inhibitors is that they may unleash excessive immune activity; the products’ labels warn about “immune-mediated adverse reactions” that can affect almost any organ system. Inflamed joints and colitis are common effects. It has therefore been considered possible that these reactions could balloon into chronic autoimmune disease, as the drug’s effects “break self-tolerance,” as Khandwala and colleagues explained.

The group pulled data from the broad TriNetX database to look at some 5.3 million patients with malignancies, among whom about 2% were given checkpoint inhibitors. Rates of new-onset RA, psoriatic arthritis (PsA), systemic sclerosis, systemic lupus erythematosus, vasculitis, and dermatopolymyositis following treatment were determined.

After propensity-score adjustment, only RA showed to develop more often in those receiving checkpoint inhibitors: 2.2% of 2,343 patients receiving checkpoint inhibitors, versus 1.8% of 84,707 treated otherwise, in the latter group’s analysis of the TriNetX medical records database. If the latter is taken as the baseline risk for RA in cancer patients, the relatively modest increase seen with checkpoint inhibitors would translate into a “number needed to harm” well into the hundreds. (It’s also noteworthy that the researchers examined six different autoimmune conditions for possible associations with checkpoint inhibitor treatment, but didn’t apply statistical corrections for the multiple tests.) As well, the authors couldn’t explain why risk for RA was heightened and yet it wasn’t for its close cousin, psoriatic arthritis, nor for any of the other conditions they considered.

Nevertheless, the researchers urged clinicians “to monitor for symptoms and signs of inflammatory arthritis, especially RA, in patients receiving [checkpoint inhibitors],” and particularly those given CTLA-4 and PDL-targeted agents in combination.

Both studies came with significant limitations, particularly the use of retrospective data that may not have included all potential influences on outcomes. Also, the CAR T-cell study had only small numbers of autoimmune disease patients; most individual diseases, including RA and lupus, were seen in just single patients.

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