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Recent advances in immunotherapy for myelodysplastic syndromes from an international perspective

 Last Update: 2022-10-25
 Source: Internet
 Author: User

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Immunotherapy has revolutionized the treatment of advanced cancers, especially solid tumors and lymphomas
.
In specific disease subsets, immunotherapy still enables patients who have failed conventional chemotherapy to achieve long-term remission
.
However, in myeloid malignancies including myelodysplastic syndrome (MDS), the therapeutic role of immunotherapy is unclear
.
Due to the anti-tumor effect of grafts, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only feasible MDS cure strategy, which also shows that enhancing tumor immunity is one of the directions of
MDS treatment exploration.
However, the complex heterogeneity of MDS also brings challenges
to the exploration of immunotherapy options.
Professor Jacqueline S.
Garcia of Dana-Farber Cancer Institute introduced the latest advances
in MDS immunotherapy from three aspects: immune checkpoint inhibitors, antibody drug conjugates and small molecule inhibitors targeting innate immune pathways.

Immune checkpoint inhibitors

Tumor cells can negatively regulate T cells through immunosuppressive receptors, thereby evading immune surveillance
.
Although numerous early trials have demonstrated the safety of immune checkpoint inhibitors such as PD-1, PD-L1, and CTLA-4 inhibitors in patients with MDS, immune checkpoint inhibitors alone or in combination have limited
efficacy in MDS patients who have not received transplantation.
Therefore, in MDS, where immunogenicity is still in question, other targets have finally proved to be more effective
.

Targeting TIM3 immune checkpoint inhibitors

TIM3 is a negative checkpoint that regulates innate and adaptive immunity, and is abnormally expressed in leukemia stem cells (LSCs) and blasts, but not in normal hematopoietic stem cells, so TIM3 is a potential therapeutic target
.
The high-affinity IgG4 anti-TIM3 antibody sabatolimab binds to TIM3, resulting in phagocytosis
killing of LSCs and blasts.
Phase 1b clinical trials of sabatolimab in combination with DNA methyltransferase (DNMT) inhibitors confirmed the safety of the combination, low immunotoxicity, and durable remission
.
Toxic events are mainly cytopenias and mild gastrointestinal reactions, including constipation and nausea
.
The results of this trial showed a moderate overall response rate (ORR), with a complete response (CR) rate of 20% and a bone marrow CR rate of 12% with hematologic improvement (HI), and a longer duration of response (DOR) (17.
1 months; 95% confidence interval [CI], 6.
7 - not achieved [NR]); The MDS subgroup with TP53 mutation also had good efficacy, with a CR rate of 29%, a bone marrow CR rate of 14% with HI, and a median DOR of 21.
5 months
.
The trial will require longer follow-up, and a randomized clinical trial of sabatolimab (STIMULUS study) is underway with better results
expected.

Targeting CD47 immune checkpoint inhibitors

In addition to T cells, the checkpoint of macrophages is also the direction
of myeloid tumors.
Tumor cells, including leukemic blasts, can bind to SIRPα via CD47 to evade phagocytosis
.
LSCs in acute myeloid leukemia (AML) express CD47 in large quantities, and the DNMT inhibitor azacitidine can induce leukemia blasts to express prophagocytosis signaling molecules
.
Magrolimab can target CD47, is a checkpoint inhibitor of macrophages, has considerable clinical activity, can lead to intravascular hemolysis; Magrolimab can enhance the ability of macrophages to clear aging platelets, and the first use requires strict treatment parameters and timely supportive treatment
of patients.

A Phase 1b clinical trial of Magrolimab in combination with azacitidine for the first-line treatment of high-risk MDS has determined the Phase II recommended dose (RP2D).

The median follow-up time in this trial was 17.
1 months (n = 95), the combined regimen had an ORR of 74.
7%, including a CR rate of 32.
6% and a bone marrow CR rate of 16.
8% with HI, a duration of CR of 11.
1 months, and a median OS was not achieved
。 In patients with MDS with TP53 mutation (n=25), the combination regimen also achieved significant efficacy, with a CR rate of 40%, a bone marrow CR rate of 12% with HI, and a median OS of 16.
3 months (10.
8-NR); the investigators considered the significant efficacy of the combination regimen in TP53 mutation subsets, possibly because macrophages do not depend on p53 activity
。 Early data from this study were so good that they prompted a Phase 3 randomized clinical trial (ENHANCE study) of azacitidine plus magrolimab versus azacitidine monotherapy for the treatment of naïve high-risk MDS
.

Antibody drug conjugates

Most MDS blasts and LSCs express CD123
.
Tagraxofusp is the first innovative drug to target CD123, which can target truncated diphtheria toxin to CD123-expressing cells; The drug has been approved by the FDA for the treatment of blastic plasmacytoid dendritic cell tumors
.
A Phase 1/2 clinical trial is evaluating the efficacy and safety
of monocytic leukemia (n = 38) as a monosomal drug monocytic uspractor.
For safety outcomes, the incidence of capillary leak syndrome (CLS) was 21%, with an 11% incidence of grade 2 and grade 3 CLS; For efficacy outcomes, median OS was 15.
6 months (95% CI, 8.
1 to 17.
5; range, 0.
36 to 40.
77).

Data from preclinical studies suggest that decreased DPH1 expression can lead to tagraxofusp resistance, but azacitidine can restore the efficacy
of tagraxofusp.
Based on this, some researchers have conducted a phase 1b clinical trial
of tagraxofusp combined with azacitidine in patients with MDS and AML.
For safety outcomes, CLS was the most common, with an incidence of 32%, of which grade 3 and grade 4 CLS occurred at 6% and 3%, respectively, mostly not severe and controllable; For efficacy results, of the first 5 high-risk MDS patients currently treated, 2 patients achieved CR and 1 achieved bone marrow CR, all 3 patients with TP53 mutation MDS
.
The trial requires longer follow-up and larger sample size to support the significant benefit
of MDS patients.

Targeting innate immune pathways

The transcriptome map of multiple types of cancer shows that the gene splicing pattern of malignant cells has changed, and mutations in the components of the basic splicing mechanism of RNA are common in MDS, especially the SF3B1, SRSF2, U2AF1 and ZRSR2 genes, which account for one-third
of all MDS.
For MDS cells carrying the IRAK4-L long subtype, the mRNA subtype of the innate immune pathway gene was changed
.
The expression of the long subtype serine/threonine kinase IRAK4 is upregulated in MDS patients with splicing mutations and is a potential therapeutic target.
CA-4948 is an orally potent small molecule IRAK4/FLT3 inhibitor
.
Data from an ongoing phase 1 clinical trial of high-risk MDS (n=43) suggest that rhabdomyolysis is a dose-limiting toxicity event; CA-4948 had an initial efficacy in MDS patients with FLT3 or splicing mutations, and the bone marrow CR rate was 57% in 7 high-risk MDS patients with splicing mutations, including 1 with hematologic improvement
.
Trials of CA-4948 in combination with venetoclax or azacitidine are being planned
.

summary

Early trial data of MDS immunotherapy, including TIM3 inhibitors, CD47 monoclonal antibodies and oral small molecule inhibitors, showed good efficacy results; However, large randomised clinical trials are needed to determine the differences
in efficacy of these regimens across MDS subgroups.
In addition, magrolimab is effective against MDS with TP53 mutation and IRAK4 inhibitors is effective against MDS with splicing mutation, a "phenomenon" that reminds investigators to carefully identify specific subpopulations
of MDS.

Reference: Jacqueline S.
Garcia.
2022 SOHO.
EXABS-140-MDS.

Reviewed by Quinta

Typesetting: Quinta

Execution: Quinta

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