Antibody immunotherapy: Current challenges and achievements

In recent years, increasing numbers of immunomodulatory antibodies have been produced with the aim of treating patients with relapsed/refractory acute myeloid leukemia (AML). Great advances have been made in this area, but a number of challenges remain. Marion Subklewe, Ludwig-Maximilians-Universität München, Munich, DE, in her talk during the eighth Annual Meeting of the Society of Hematologic Oncology (SOHO), discussed the current antibodies (Abs) targeting AML that are available and future prospective agents.

Available Ab-based immunotherapy platforms

Currently, the main types are:

• Abs with engineered Fc domain
• Ab–drug conjugates (ADCs)
• T-cell recruiting constructs
• Checkpoint inhibitors
• T-cell recruiting Abs

An ideal target antigen (Ag) in AML must be expressed on the bulk of the leukemia cells and also the leukemic stem cells, while ideally not being expressed on normal hematopoietic cells. The heterogeneity of AML tumor cells both inter- and intraindividual makes finding such an antigen a challenge. Current targets are lineage Ags rather than leukemia-specific Ags.

One of the most common targets is CD33. It is highly expressed in AML cells (> 99%) however it is also expressed by normal blood cells, in particular macrophages and dendritic cells. This lack of specificity can result in the common adverse events of anemia and neutropenia. This is a frequent problem with many of the Ags considered for targeting in AML.

So far, no unconjugated monoclonal Abs have been successful in the clinic for treating AML and only a few have advanced to clinical trials.

Antibody–drug conjugates

Gemtuzumab ozogamicin (GO) is the only ADC approved for treatment of AML in newly diagnosed CD33⁺ adult patients in combination with 7+3 chemotherapy. The U.S. Food and Drug Administration (FDA) have also approved GO for use as a single agent in newly diagnosed patients along with relapsed/refractory CD33⁺ adult or pediatric (≥ 2 years) AML. GO provides the most benefit in terms of outcome for patients with standard risk disease, however little improvement is seen in high-risk cases. If you want to read more on this subject, an additional case report regarding GO that was published on the AML Hub can be found here.

Checkpoint inhibitor Abs

These act by blocking the receptor ligand interaction, and target molecules include the following:

• PD1/PDL1 is most commonly targeted; agents include nivolumab and pembrolizumab and are the subject of the majority of clinical trials.
• CD47 mediates the “don’t eat me” signal on AML cells. Blocking this signal promotes phagocytosis of target cells, making it an interesting candidate for new agents.
• CD70 is an immune-modulating Ag that interacts with CD27 on T cells.

Nivolumab, in combination with azacitidine, produced positive results in the high-risk population tested, doubling the expected overall survival time from 5−7 months to 12 months. Patients showing signs of bone marrow infiltration (CD3 and CD8 cells present pre-therapy) showed higher response rates. This indicates the potential use of bone marrow inflammation as a biomarker in these patients.

CD47 is an innate inhibitory checkpoint that is overexpressed on AML cells and therefore makes an ideal target. Magrolimab represents an anti-CD47 Ab that has achieved positive results in combination with azacitidine in myelodysplastic syndromes and AML. In myelodysplastic syndromes, an overall response rate of 92% was recorded and this was 64% in AML, both achieving ≥ 50% complete response (CR)/CR with incomplete hematological recovery (CRi). A notably high response rate was identified in TP53-mutated patients (78% CR).

CD70 has been identified on AML bulk and leukemic stem cells but is absent on normal hematopoietic cells. Cusatuzumab is an anti-CD70 Ab that has progressed to phase I/II trials with azacitidine. Out of a small group of 12 patients, ten responded (CR + CRi) and CR was achieved in 67% overall.

To listen to Naval Daver discuss which patients with AML benefit from the use of checkpoint inhibitors, please see here.

Clinical trials with bispecific T-cell engagers (BiTEs®)

AMG 330 is a CD33 BiTE tested in a phase I trial of adults ≥ 18 years (N = 60) with relapsed/refractory AML who had received ≥ 1 previous therapy. The primary endpoints of this trial were to assess the safety and tolerability of AMG 330 and identify a dose for a phase II trial.

In this group of patients with advanced disease and a majority adverse cytogenetic risk profile (62%), eight patients responded to therapy (CR, n = 2; CRi, n = 4; one morphologic leukemia-free state). A dose of 120 μg/day was established in those achieving CR/CRi. In terms of the safety profile, cytokine release syndrome was seen in 67% of cases and was the most common adverse event recorded. However, only 16% of events were Grade 3 or greater.

Another anti-CD33 BiTE examined in a phase I trial (NCT03224819) is AMG 673, which aims to overcome the issues with AMG 330 having a short half-life with the addition of a half-life extender Fc domain. This addition increases the half-life from less than 2 hours to 2 days. A total of 30 patients were included in this study. The study found that the grade of CRS was correlated with the number of blasts present in the bone marrow along with AMG 673 exposure. A reduction in blasts was seen in 41% of patients.

Flotetuzumab, a bispecific anti-CD3 and -CD123 molecule, has advanced the furthest in clinical testing having reached a phase II trial. In patients who were primary refractory, a clear benefit was seen. In this difficult to treat cohort, 29.4% achieved CR/CRi, which compares very favorably with the current standard of 13% CR/CRi. An overall response rate of 35.3% was observed.

In the future, T-cell recruiting Ab constructs that can recognize intracellular Ags in the presence of major histocompatibility complex molecules could increase targeting of cytotoxicity to AML cells and increase the number of possible targets that could be used in designing new therapeutics.

For further information on BiTEs, please see an overview from the AML Hub here.

Challenges in bispecific T-cell recruiting Ab constructs

• Ag sink
• T-cell activation

An Ag sink, where the antigen of interest expressed on normal hematopoietic stem cells binds the active agent and therefore prevents binding of the Ag on tumor cells, is seen in preclinical studies when using non-ADCs. This phenomenon may contribute to the difficulty in achieving levels in the serum that can produce a response and explain why there is a delay in reaching the desired concentration.

In order to achieve T-cell activation, a costimulatory domain is required. These are not present when T-cell recruiting Ab constructs are used. The addition of a positive costimulatory molecule such as CD80 or CD86 can markedly increase both the cytotoxicity achieved and T-cell proliferation.

While this result initially seems positive, a reactionary upregulation of inhibitory checkpoint molecule PD-L1 is seen. An additional checkpoint inhibitory T-cell engager can be used to combat the adaptive immune resistance.

Conclusion

The use of modified Abs to treat AML is an exciting area that is still evolving. The ongoing clinical trials have provided positive data on the safety of these Abs, however the efficacy levels are still lower than desired. The antigenic profile of AML cells needs to be examined further for candidate targets to create agents that can achieve measurable residual disease negativity.