Jared Kaltwasser

 (MM) remains an incurable disease, but advances in our understanding of natural killer (NK) cells may provide new avenues by which to combat it.

The latest findings in NK cell research and their potential to be used in MM therapy were discussed in 

Corresponding author Tony Reiman, MD, of the University of New Brunswick, and colleagues, explained that a wide array of emerging therapies, such as proteasome inhibitors, immunomodulatory drugs, and novel combination therapies, have significantly improved outcomes in patients with MM, but that the high rate of eventual relapse and the heterogeneity of the disease among patients have made it a particularly difficult cancer to fight.

“Additionally, MM is considered a disease of the immune system,” the investigators wrote. “Gradual immune dysregulation and impairment of NK cells, T cells, B cells, and dendritic cells allow malignant plasma cells to escape immunosurveillance.”

Reiman and colleagues proposed that a better understanding of the immune environment of MM could lead to strategies to reengage the immune system to inhibit MM growth. This is where NK cells potentially come into play.

These cells are considered the most active subset of innate lymphoid cells. Their name comes from their ability to target infected and malignant cells without prior sensitization. They cells have both activating and inhibitory receptors (IRs), and their activity is controlled by signals between the receptors.

One strategy for leveraging NKs is to use monoclonal antibodies to target IRs. This approach has shown benefits in other types of cancers, the authors wrote, and there is emerging evidence suggesting it is a viable option in MM as well.

They advocated paying particular attention “to understanding the heterogeneity of ligand expression both within and across patients with MM, the interplay between NK and T cells in response to IR blockade therapy, and how NK-targeted therapy can be combined with existing therapeutic options in MM patients.”

The authors said notable research has been published suggesting a role for several other IRs in MM biology: KIRs, NKG2A, TIGIT, TIM-3, PD-1, and LAG-3.

Of those, Reiman and colleagues singled out KIRs as the “most promising” target.“Not only were anti-KIR antibodies shown to be well tolerated, but they were also shown to enhance NK cell function,” they wrote.

Some of those IRs are also expressed on T cells, meaning therapies that target those receptors might boost the anticancer effects of both types of cells; however, the authors said most studies into the IRs have focused almost exclusively on T cells while ignoring NK cells.

Early failure of some clinical trials of IR blockades is likely due to intra- and interpatient heterogeneity, the authors noted. Any kind of IR-blockade therapy would likely need to be tailored to each particular patient’s expression of receptors, the investigators said, similar to what is done in solid tumors.

The investigators closed with a list of key steps they believe will need to be undertaken to bring NK-based therapy for MM close to fruition. Among those steps:

Profile NK cell receptors, subpopulations, cell activity, and cell function in MM

Profile the expression of NK cell receptor cognate ligands

Explore the integration of NK cell–based therapies and traditional therapies preclinically in order to optimize clinical trial design.

Alfarra H, Weir J, Grieve S, Reiman T. Targeting NK cell inhibitory receptors for precision multiple myeloma immunotherapy. 

. Published online November 12, 2020. doi:10.3389/fimmu.2020.575609

Articles

Emerging research into natural killer cells has shown promise, but the findings are complicated by the heterogeneity of multiple myeloma (MM).

Natural Killer Cells Could Play Key Role in Fight Against MM

Patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA) experience equivalent declines in hand function, according to a new study, but investigators also found that psoriasis itself causes similar impairment of the hands.

, raises new questions about links between psoriasis and arthritis.

Both PsA and RA have well-documented impacts on patients’ physical functioning, but less has been published related to how the loss of hand function experienced by patients with RA compares with that of other diseases, according to corresponding Anna-Maria Liphardt, PhD, of the Friedrich-Alexander University Erlangen Nürnberg and University Clinic Erlangen, in Germany, and colleagues.

“The impact of inflammatory arthritis on hand function has mainly been studied in RA,” they said, “and studies comparing hand function in these diseases are sparse.”

Liphardt and colleagues therefore decided to comprehensively evaluate hand function in PsA and RA side by side, by looking at objective strength measures and also patient perceptions of hand function. In addition to comparing these measures in the 2 disease categories, the authors also compared them with healthy controls.

In the study, 299 subjects were enrolled, split nearly evenly between patients with RA (101 patients), patients with PsA (92 patients), and nonarthritic controls (106 patients). The nonarthritic patient arm was made up of 51 patients with psoriasis and 55 healthy controls.

The patients were assessed using a number of measures. A hand dynamometer was used to measure isometric grip strength. The Moberg-Picking-Up Test (MPUT) was used to assess fine-motor skills, and patients were also timed to see how long it took them to move 12 small items from a table into a box with their eyes opened. Lastly, patients were asked to rate their own hand function using the Michigan Hand Questionnaire (MHQ). Data were taken for both hands, but the investigators noted which hand was a patient’s dominant hand.

The investigators found that sex, age, disease group, and hand dominance all affected hand function. However, PsA and RA appeared to have similar influences on hand function, and in both cases the impact was greater for women than men. 

“We found that the impact of disease on hand function is particularly pronounced in older subjects, suggesting that younger individuals are better in functionally compensating their diseases,” they said. “This may be caused by generally better muscular performance and neuromuscular interaction in younger individuals, but also by disease management of RA and PsA in the last two decades.”

However, the authors also reported something they did not expect: Patients with psoriasis were experiencing significantly altered hand function.

“Although these patients did not show any clinical signs of PsA, hand function was clearly impaired and mirrored that in patients with RA and PsA but not in healthy controls,” they said.

Liphardt and colleagues said the finding suggests psoriasis patients “exhibit a functional arthritis-like phenotype.”

“Such observations back concepts that patients with psoriasis show an altered stress response not only in the skin but also in the musculoskeletal structures,” they said.

The investigators added that it is possible that functional changes in patients with psoriasis might be indicative of a more pronounced progression to PsA, but they said the question would need to be investigated with further studies.

Liphardt AM, Manger E, Liehr S, et al. Similar impact of psoriatic arthritis and rheumatoid arthritis on objective and subjective parameters of hand function. 

. 2020;2(12):734-740. doi:10.1002/acr2.11196

In an unexpected finding, patients with psoriasis showed similar hand impairment to patients with psoriatic arthritis and rheumatoid arthritis.

Psoriatic Arthritis, Rheumatoid Arthritis Cause Similar Hand Impairment, but So Does Psoriasis 

A new study suggests that ruxolitinib (Jakafi) may help mitigate steroid-refractory cytokine release syndrome (CRS) in children who receive chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoblastic leukemia (B-ALL).

Journal of Cellular and Molecular Medicine

CAR T-cell therapy has been a promising advancement in a number of malignancies, including B-ALL, the most common type of cancer in children. However, the therapy has been associated with significant adverse effects, including CRS and immune effector cell–associated neurotoxicity syndrome (ICANS).

Investigators including corresponding author Xiaoming Feng, PhD, of the Chinese Academy of Medical Sciences and Peking Union Medical College, noted that the typical treatment for patients who suffer CRS or ICANS involves drugs like tocilizumab (Actemra) along with steroids. In cases of CRS grade 3 or higher, high-dose steroids are recommended, and high-dose methylprednisolone is recommended for refractory CRS. Unfortunately, those therapies do not always work, and their failure can pose a major barrier to patient survival.

“[L]ife-threatening consequences may occur if severe CRS cannot be controlled by current regimens,” the investigators said.

In hopes of providing another therapeutic avenue, Feng and colleagues turned to ruxolitinib, which is a Janus kinase 1 and 2 inhibitor. These kinases play a role in transmitting cytokine-induced signals and thus have become a target for a number of inflammatory diseases. The drug has already been approved for the treatment of steroid-refractory graft-vs-host disease, prompting hopes that it might be a meaningful intervention in other conditions, such as severe CRS.

The new study was a pilot study that involved just 14 patients, but the results were uniform.

Each patient in the study had received CD19 or CD22 CAR T-cell therapies, and 4 of those patients went on to develop grade 3 or higher CRS that could not be alleviated with high-dose steroids.

Each of those 4 patients was then administered oral ruxolitinib (5 mg twice daily). The results were rapid and convincing.

“CRS-related cytokines including IL-6, IL-10, sCD25, TNF‐γ, and SF quickly decreased in these four patients after ruxolitinib intervention, which implicates that ruxolitinib successfully stops these cytokines’ release,” the authors said.

In addition to the decrease in CRS symptoms, serum cytokines also decreased significantly.

At 30 days post CAR T-cell infusion, each patient had achieved complete remission, and the investigators were still able to detect CAR T expansion in vivo. No obvious adverse events were reported related to ruxolitinib.

There was, however, a caveat to the findings. Despite the positive in vivo results, in vitro assays suggested that ruxolitinib could dampen CAR T expansion and cytotoxicity.

“This discrepancy may be due to the presence of excretive systems or an intermediate cellular part in humans which await future clarification,” the authors said.

They added that their data also showed that ruxolitinib has a stronger impact on CAR T effector function than dexamethasone.

“Ruxolitinib mainly inhibits CAR T cell expansion and releasing of T cell cytotoxicity related cytokine (INF‐γ and Granzyme B) in vitro,” they said. “It would be interesting to measure INF‐γ and Granzyme B in patients with CAR T cell therapy in future study.”

In the meantime, the authors said physicians should carefully consider the timing and dosage of ruxolitinib in patients with steroid-refractory CRS in order to avoid dampening the anti-leukemia response.

Pan J, Deng B, Ling Z, et al. Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy. 

. Published online December 12, 2020. doi:10.1111/jcmm.16176

A small pilot study could point the way to a new option for patients with B-cell acute lymphoblastic leukemia (B-ALL) who experience cytokine release syndrome (CRS) that cannot be cured with the standard therapy. 

Small Study Shows Ruxolitinib Helps Severe Steroid-Refractory CRS in Patients With B-ALL

High levels of xylitol and glycolic acid appear to correlate with longer progression-free survival (PFS) in patients with 

 (MM) and xylitol may be a good candidate for a novel therapy, according to a new study.

MM is highly heterogeneous and ultimately incurable, resulting in a significant push for better diagnostic and prognostic tools, as well as the need for novel therapies.

Corresponding author Xiaojin Wu, PhD, of Soochow University, in China, and colleagues, sought to better understand MM through the use of metabolic profiling. Their findings were published in the 

Metabolomics has already been used as a novel diagnostic tool in several types of cancer, including pancreatic, renal, and oral cancer. In order to evaluate metabolic profiling’s efficacy in MM, Wu and colleagues decided to compare the metabolic profiles of healthy controls to those of patients with MM using untargeted gas chromatography-mass spectrometry (GC-MS). Their hope was to identify links between particular metabolites and clinical characteristics, therapeutic efficacy, and disease prognosis.

The investigators recruited 55 patients with newly diagnosed MM and 37 healthy controls between August 2016 and October 2017. After conducting serum metabolic profiling, 27 metabolites were identified as significantly different between the MM and control cohorts. Eleven of those metabolites were significantly elevated in patients with MM, while the remaining 16 were significantly decreased.

Among their findings, patients with renal impairment and bone destruction tended to undergo particular metabolic changes. Urea levels were significantly decreased following treatment, and post-treatment hypotaurine increases correlated with a positive response to therapy. 

“Levels of hypotaurine were decreased at diagnosis in MM patients,” Wu and colleagues wrote. “After treatment, levels of hypotaurine increased significantly in patients with good outcomes, but was still very low in patients with ineffective treatment, which suggests that low levels of hypotaurine may have a certain relationship with the occurrence of MM.”

However, multivariate analysis identified high cysteine and high hypotaurine prior to therapy as independent risk factors for poor treatment outcomes.

Conversely, high levels of glycolic acid and xylitol were found to correlate with a lower risk of disease progression.

In the case of glycolic acid, the authors noted that it is a known inhibitor of tyrosinase, and that Janus kinases 1 and 2 overexpression has been linked with MM. Preclinical studies of JAK inhibitors have shown promise against MM, they noted, a fact that appears to mesh with the current study’s finding that glycolic acid levels correlate with PFS.

“Whether the increased levels of glycolic acid are related to JAK signaling pathway and the prognosis of multiple myeloma patients is not clear, and needs to be investigated further,” they said.

Xylitol is less well studied when it comes to its effect on cancer cells, though Wu and colleagues noted that high concentrations of xylitol are required to inhibit the growth of normal cells, which they said suggests it is more cytotoxic for cancer cells.

“More studies confirmed the inhibitory effect of xylitol with a variety of cell lines,” they wrote. “Moreover xylitol induced cell morphological changes and autophagy in lung cancer cells.”

The authors said xylitol could warrant further study as a therapeutic target in MM.

Zhao R, Xie Y, Yang B, et al. Identification of metabolic biomarkers to predict treatment outcome and disease progression in multiple myeloma. 

. 2020;10(11):3935-3946. Published online November 1, 2020.

New research shows metabolic biomarkers could be meaningful tools for predicting treatment outcomes in patients, based on a comparison of biomarkers, clinical characteristics, and therapeutic efficacy. 

 

Jared Kaltwasser

Articles

Natural Killer Cells Could Play Key Role in Fight Against MM

Psoriatic Arthritis, Rheumatoid Arthritis Cause Similar Hand Impairment, but So Does Psoriasis

Small Study Shows Ruxolitinib Helps Severe Steroid-Refractory CRS in Patients With B-ALL

Metabolic Biomarkers Could Predict Prognosis, Treatment Outcomes in MM