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Hct hematology. T Cell Reloading After Allogeneic HCT: Enhancing Immunotherapy for AML Relapse

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How does flotetuzumab impact MHC class II expression in AML cells. What role do T cell-engaging therapies play in treating AML relapse after allogeneic HCT. Why is upregulation of MHC class II molecules significant for immunotherapy effectiveness. What challenges exist in treating AML relapse following allogeneic transplantation.

The Significance of MHC Class II Upregulation in AML Immunotherapy

Acute myeloid leukemia (AML) remains a challenging disease to treat, especially when relapse occurs after allogeneic hematopoietic cell transplantation (alloHCT). Recent research has shed light on promising immunotherapeutic approaches that may enhance the body’s ability to fight AML relapse. A key finding centers on the upregulation of major histocompatibility complex (MHC) class II molecules on AML cells through interferon-gamma (IFNγ) signaling.

Why is MHC class II upregulation important? MHC class II molecules play a crucial role in presenting antigens to T cells, thereby activating the immune response against cancer cells. When AML cells express higher levels of MHC class II, they become more visible to the immune system, potentially making them more susceptible to attack by T cells.

Mechanisms of MHC Class II Upregulation

Research has shown that T cell-engaging therapies, such as the dual-affinity retargeting (DART) compound flotetuzumab (FLZ) and chimeric antigen receptor T (CAR-T) cells targeting AML-associated antigens, can induce the upregulation of MHC class II molecules. This occurs through the following mechanism:

  1. T cell-engaging therapies activate T cells to target AML cells
  2. Activated T cells release interferon-gamma (IFNγ)
  3. IFNγ signaling triggers upregulation of MHC class II molecules on AML cells
  4. Increased MHC class II expression enhances antigen presentation and immune recognition

Flotetuzumab: A Promising T Cell-Engaging Therapy for AML

Flotetuzumab (FLZ) has emerged as a promising immunotherapeutic agent for treating AML relapse after alloHCT. As a CD123-targeting DART molecule, FLZ works by bringing T cells into close proximity with AML cells, facilitating immune-mediated killing.

How does flotetuzumab enhance the immune response against AML? The mechanism involves:

  • Binding to CD123 on AML cells and CD3 on T cells
  • Activating T cells to release cytokines, including IFNγ
  • Inducing MHC class II upregulation on AML cells through IFNγ signaling
  • Increasing visibility of AML cells to the immune system

This dual action of direct T cell engagement and enhancement of antigen presentation makes flotetuzumab a potentially powerful tool in combating AML relapse.

CAR-T Cell Therapy: Another Avenue for AML Immunotherapy

Chimeric antigen receptor T (CAR-T) cell therapy represents another innovative approach to treating AML relapse. CAR-T cells are engineered to target specific antigens on AML cells, such as CD123, CD33, and CD371.

How do CAR-T cells contribute to MHC class II upregulation? Similar to flotetuzumab, CAR-T cells targeting AML-associated antigens can:

  • Directly engage and kill AML cells
  • Release IFNγ upon activation
  • Induce paracrine IFNγ signaling in the tumor microenvironment
  • Trigger upregulation of MHC class II molecules on surviving AML cells

This mechanism suggests that CAR-T cell therapy may not only directly eliminate AML cells but also enhance the visibility of remaining leukemia cells to the immune system, potentially leading to a more robust and sustained anti-leukemic response.

Challenges in Treating AML Relapse After Allogeneic HCT

Despite the potent graft-versus-leukemia (GVL) effects mediated by donor-derived cells in allogeneic HCT, AML relapse remains a significant challenge. Several factors contribute to the difficulty in treating post-transplant relapse:

Immune Evasion Mechanisms

AML cells can develop various strategies to evade immune recognition and attack. These may include:

  • Downregulation of MHC molecules
  • Expression of immune checkpoint molecules
  • Induction of peripheral tolerance
  • Loss of mismatched human leukocyte antigen haplotypes

Genetic Instability

The inherent genetic instability of AML progenitor cells can lead to the emergence of resistant clones that are less susceptible to immune-mediated killing. This genetic plasticity allows AML cells to adapt to the selective pressures imposed by allo-reactive effector cells.

Limited Treatment Options

Conventional treatments for AML relapse after alloHCT often have limited efficacy and may be associated with significant toxicities. This underscores the need for novel therapeutic approaches that can effectively target resistant AML cells while minimizing harm to healthy tissues.

The Promise of Combining Immunotherapies for AML Relapse

The findings on MHC class II upregulation by T cell-engaging therapies open up exciting possibilities for combination treatment strategies. By leveraging the complementary mechanisms of different immunotherapeutic approaches, it may be possible to create more effective and durable responses in patients with relapsed AML.

Potential Combination Strategies

  • Flotetuzumab + CAR-T cells: Combining these therapies could lead to enhanced T cell activation and more robust MHC class II upregulation.
  • Immunotherapy + Epigenetic modifiers: Drugs that influence gene expression could potentially further enhance MHC class II expression on AML cells.
  • T cell-engaging therapies + Checkpoint inhibitors: This combination might help overcome immune suppression mechanisms and boost the overall anti-leukemic response.

By strategically combining these approaches, clinicians may be able to create a more hostile environment for AML cells, making it harder for them to evade immune recognition and elimination.

Translating Research Findings into Clinical Practice

The promising results observed with flotetuzumab and CAR-T cell therapies in preclinical studies and early clinical trials raise important questions about how to best translate these findings into effective treatments for patients with relapsed AML after alloHCT.

Key Considerations for Clinical Implementation

  • Patient selection: Identifying which patients are most likely to benefit from T cell-engaging therapies based on their disease characteristics and immune profile.
  • Timing of intervention: Determining the optimal time to initiate immunotherapy after alloHCT to maximize efficacy while minimizing the risk of graft-versus-host disease.
  • Monitoring and biomarkers: Developing robust methods to track MHC class II expression and other relevant biomarkers to guide treatment decisions and assess response.
  • Managing toxicities: Implementing strategies to mitigate potential side effects associated with T cell-engaging therapies, such as cytokine release syndrome.

As research in this area continues to evolve, it will be crucial to design well-controlled clinical trials that can definitively establish the efficacy and safety of these novel immunotherapeutic approaches in the post-alloHCT setting.

Future Directions in AML Immunotherapy Research

The discovery of MHC class II upregulation as a mechanism of action for T cell-engaging therapies opens up numerous avenues for future research in AML immunotherapy. Some promising areas of investigation include:

Enhancing MHC Class II Expression

Researchers may explore additional methods to boost MHC class II expression on AML cells, such as:

  • Developing targeted therapies that directly induce MHC class II upregulation
  • Investigating the role of epigenetic modifiers in enhancing antigen presentation
  • Exploring combination strategies that synergistically increase MHC class II expression

Optimizing T Cell-Engaging Therapies

Future studies may focus on refining existing T cell-engaging therapies and developing new ones, with goals such as:

  • Improving the specificity and affinity of bispecific antibodies like flotetuzumab
  • Enhancing the persistence and efficacy of CAR-T cells in the AML setting
  • Developing novel constructs that can simultaneously target multiple AML-associated antigens

Understanding Resistance Mechanisms

As these therapies move forward in clinical development, it will be crucial to investigate potential resistance mechanisms that may emerge, including:

  • Alterations in IFNγ signaling pathways
  • Development of escape variants with reduced target antigen expression
  • Upregulation of inhibitory immune checkpoints in response to therapy

By proactively studying these resistance mechanisms, researchers can develop strategies to overcome them and maintain long-term efficacy of immunotherapeutic approaches.

Implications for Broader Cancer Immunotherapy

While the current research focuses on AML, the principles underlying MHC class II upregulation through T cell-engaging therapies may have broader implications for cancer immunotherapy as a whole. This mechanism could potentially be exploited in other hematologic malignancies and solid tumors where enhancing antigen presentation could improve immune recognition and elimination of cancer cells.

Potential Applications in Other Cancers

  • Lymphomas: Investigating whether similar approaches could enhance the efficacy of CAR-T cell therapies in B-cell malignancies
  • Solid tumors: Exploring the potential of T cell-engaging therapies to increase MHC class II expression and improve immunogenicity in cancers such as melanoma or lung cancer
  • Combination with other immunotherapies: Studying how MHC class II upregulation might synergize with checkpoint inhibitors or cancer vaccines across various tumor types

As our understanding of the complex interplay between cancer cells and the immune system continues to grow, the insights gained from AML research may pave the way for more effective immunotherapeutic strategies across a wide range of malignancies.

In conclusion, the discovery of MHC class II upregulation as a mechanism of action for T cell-engaging therapies represents a significant advance in our understanding of AML immunotherapy. This finding not only provides a strong rationale for the use of therapies like flotetuzumab and CAR-T cells in the post-alloHCT setting but also opens up new avenues for combination strategies and future research. As we continue to unravel the complexities of the immune response to AML, we move closer to developing more effective and personalized treatment approaches for patients facing this challenging disease.

T cells reloaded after allogeneic HCT | Blood

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IMMUNOBIOLOGY AND IMMUNOTHERAPY|
April 6, 2023

Martin Bornhäuser

Blood (2023) 141 (14): 1652–1653.

https://doi.org/10.1182/blood.2022019106

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A related article has been published:
Flotetuzumab and other T-cell immunotherapies upregulate MHC class II expression on acute myeloid leukemia cells


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Citation

Martin Bornhäuser; T cells reloaded after allogeneic HCT. Blood 2023; 141 (14): 1652–1653. doi: https://doi.org/10.1182/blood.2022019106

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In this issue of Blood, Rimando et al suggest that T-cell–engaging immunotherapeutic approaches may be especially suited to confront or respond to or salvage relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (alloHCT).1 Both the dual-affinity retargeting (DART) compound flotetuzumab (FLZ) and chimeric antigen-receptor T (CART) cells against AML-associated surface antigens such as CD123, CD33, and CD371 induced upregulation of major histocompatibility complex (MHC)-class II molecules by interferon-gamma (IFNγ) signaling. This mechanism was confirmed in cell lines and primary AML cells in vitro, in xenogeneic transplant models, and in samples of patients treated with FLZ for relapsed disease. By elucidating the mode of action, the authors provide further rational for use of T cell–engaging therapies and/or CART cells in patients with relapse after alloHCT.

AlloHCT is the most effective strategy for treating suitable patients with AML, owing to the potent graft-versus-leukemia (GVL) effects mediated by donor-derived, allo-reactive effector cells. In vitro cytotoxicity studies of matched donor cells with AML blasts and adoptive transfer studies in NSG mice support the hypothesis that MHC class II molecules are major targets of GVL.2 Despite the strength of allogeneic GVL effects, a significant proportion of patients with AML relapse after alloHCT. Treatment of relapse after alloHCT is an immense challenge, and a cure is elusive in most cases.3 The exact reason for immune escape is difficult to dissect at an individual case level, but several patterns of immune evasion have been described. Peripheral tolerance-induction and expression of immune checkpoints on leukemic cells after alloHCT may contribute to the loss of antileukemic immunity resulting in frank relapse.4 Due to inherent genetic instability, AML progenitor cells, like many other cancer cells, can downregulate MHC molecules. The mode and pattern of reduced human leukocyte antigen expression are shaped mainly by the pressures induced by allo-reactive effector cells. Complete loss of mismatched human leukocyte antigen haplotypes on the genetic level has been described after haploidentical alloHCT.5 Conversely, posttranscriptional downregulation of MHC class II expression has been detected on AML blasts at relapse after allogeneic HCT. In that same study, the incubation of leukemic cells with IFNγ led to upregulation of MHC class II expression.6 

This report opens up a new and exciting strategy for treatment of relapsed AML after alloHCT. The authors of this study clearly demonstrate that both the CD123-targeting DART FLZ and AML-targeting CART cells induce paracrine IFNγ and subsequent upregulation of MHC class II (see figure). This effect was observed not only in vitro but also in a xenotransplant model and in paired patient samples analyzed before and after treatment with FLZ.

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Acute myeloid leukemia (AML) targeted by either the dual-affinity retargeting compound (DART) flotetuzumab (FLZ) or chimeric-antigen-receptor (CAR) T cells upregulate major histocompatibility complex (MHC) class II on their surface, rendering them recognizable by allogeneic effector cells in patients after allogeneic hematopoietic cell transplantation. GvL, graft-versus-leukemia; IFNγ, interferon gamma; TCR, T-cell receptor. Illustration by Helena Jambor.

View largeDownload PPT

Acute myeloid leukemia (AML) targeted by either the dual-affinity retargeting compound (DART) flotetuzumab (FLZ) or chimeric-antigen-receptor (CAR) T cells upregulate major histocompatibility complex (MHC) class II on their surface, rendering them recognizable by allogeneic effector cells in patients after allogeneic hematopoietic cell transplantation. GvL, graft-versus-leukemia; IFNγ, interferon gamma; TCR, T-cell receptor. Illustration by Helena Jambor.

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This study provides a clear rationale to test T-cell–engaging therapies in patients with relapse after alloHCT. An interesting question to answer is whether the effects of these therapies are more durable in such patients, compared to their effects in patients who have not undergone a transplantation procedure.7 This benefit is suggested by prior reports that unspecific reactivation of donor T cells—for example, after adoptive transfer—has been shown to be of limited efficacy, but durable, in a small subset of patients.8 The limitation of adoptive transfer always has been the potential induction of graft-versus-host disease (GVHD). Such an on-target, off-tumor toxicity has to be kept in mind when T cells are activated or transferred after alloHCT and MHC expression is induced, but the risk of GVHD induction, it is hoped, will be lower when the awakening of alloreactivity is targeted to AML cells. With the importance of IFNγ signaling for the observed effects, one has to be cautious when patients have received or are still on JAK-2 inhibitors (eg, ruxolitinib). However, the additional systemic administration of IFNγ might even boost the effects of T-cell–targeting therapies. Fortunately, we will not have to wait too long to get first insights into the feasibility and efficacy of such treatment strategies, as the use of both IFNγ and FZL are currently being tested in patients with relapse after alloHCT (https://clinicaltrials.gov: NCT04628338 and NCT04582864). As the response to FLZ has been shown to be related to expression of IFNγ-related genes in the nontransplant setting, a point of interest is whether similar predictive biomarkers can be identified in the post-HCT setting.9 The current paper by Rimando et al provides a convincing rationale to pursue the clinical testing of T-cell–engaging therapies and CART approaches in patients with relapse of myeloid malignancies after alloHCT.

Conflict-of-interest disclosure: M.B. reports being a scientific advisory board member of and receiving speaker honoraria from Jazz Pharmaceuticals and MSD.

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