The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients

Friedrich, Mirco; Neri, Paola; Kehl, Niklas; Michel, Julius; Steiger, Simon; Kilian, Michael; Leblay, Noémie; Maity, Ranjan; Sankowski, Roman; Lee, Holly; Barakat, Elie; Ahn, Sung Gwe; Weinhold, Niels; Rippe, Karsten; Bunse, Lukas; Platten, Michael; Goldschmidt, Hartmut; Müller‐Tidow, Carsten; Raab, Marc-Steffen; Bahlis, Nizar J.

doi:10.1016/j.ccell.2023.02.008

Cited by 110 publications

(51 citation statements)

References 58 publications

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“…Patients relapsing with retained antigen expression showed highly expanded yet exhausted T cells in their tumor microenvironment in line with de cits in their effector cell compartment. In an elegant study, dysfunctional hyper-expanded T cell clonotypes were linked to resistance to bispecs 31 . Treatment-free intervals reinvigorate exhausted T cells in another study on bispecs 32 .…”

Section: Discussionmentioning

confidence: 99%

Sequential Antigen-loss and Branching Evolution in Lymphoma after Anti-CD19 and Anti-CD20 Targeted T Cell Redirecting Immunotherapy

Rasche

Duell

Leipold

et al. 2023

Preprint

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CD19 CAR T cells and CD20 targeting T cell engaging bispecific antibodies have been approved in B-cell Non-Hodgkin lymphoma lately, heralding a new clinical setting where patients are treated with both approaches, sequentially. The aim of our study was to investigate the selective pressure of CD19 and CD20 directed therapy on the clonal architecture in lymphoma. Using a broad analytical pipeline, we identified truncating mutations in the gene encoding CD20 conferring antigen loss in 80% of patients relapsing from CD20 bispecs. Pronounced T cell exhaustion was identified in cases with progressive disease and retained CD20 expression. We also confirmed CD19 loss after CAR T cell therapy and report the case of sequential CD19 and CD20 loss. We observed branching evolution with re-emergence of CD20-positive subclones at later time points and spatial heterogeneity for CD20 expression in response to targeted therapy. Our results highlight immunotherapy as an evolutionary bottleneck selecting for antigen-loss variants but also complex evolutionary pathways underlying disease progression from these novel therapies.

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Section: Discussionmentioning

confidence: 99%

Sequential Antigen-loss and Branching Evolution in Lymphoma after Anti-CD19 and Anti-CD20 Targeted T Cell Redirecting Immunotherapy

Rasche

Duell

Leipold

et al. 2023

Preprint

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“…Several studies have shown that high tumor burden and presence of extramedullary disease is associated with an inferior response to BsAbs [35], [39]. In addition, a high number of regulatory T-cells or high proportion of exhausted T-cells is associated with failure to respond to BsAb treatment [25], [66], [67]. Disease progression may be related to loss of target antigen expression or development of T-cell exhaustion due to continuous BsAb-mediated T-cell activation [62], [68].…”

Section: What Are Resistance Mechanisms To Bispecific Antibodies?mentioning

confidence: 99%

T‐cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions

O'Neill

Donk

2023

eJHaem

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T‐cell engaging bispecific antibodies (BsAbs) have substantial activity in heavily pretreated patients with multiple myeloma (MM). The overall response rate obtained with B‐cell maturation antigen (BCMA)‐targeting BsAbs is approximately 60%–70%, including a high proportion of patients achieving very good partial response or complete response. Comparable efficacy is seen with BsAbs targeting GPRC5D or FcRH5. Cytokine release syndrome is frequently observed with BsAb treatment, but mostly during the step‐up doses and the first full dose. Early intervention with IL‐6 receptor blocking antibodies (e.g., tocilizumab) prevents escalation to severe manifestations. Infections are also common during treatment and related to the extent of exposure to immune suppressive anti‐MM agents, as well as development of hypogammaglobulinemia due to elimination of normal plasma cells, and probably because of T‐cell exhaustion resulting from continuous BsAb‐mediated T‐cell activation. Adequate monitoring for infections and institution of infectious prophylaxis are essential. Patients treated with GPRC5D‐targteing BsAbs often develop skin and nail disorders and loss of taste, which is likely related to GPRC5D expression in cells that produce hard keratin. Currently ongoing studies are aiming at further improving these results by evaluating BsAbs in combination with other drugs, such as immunomodulatory agents and anti‐CD38 antibodies, as well as the application of BsAbs in earlier lines of therapy, including patients with newly diagnosed disease. We expect that the outcomes of patients with MM will further improve by the introduction of this novel type of T‐cell immunotherapy.

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“…Friedrich et al determined the immunological single-cell mechanisms of resistance to bispecific BCMAxCD3 T-cell engager (TCE) therapy, a novel immunotherapy leading to unprecedented response rates in refractory MM. 14 They show that TCEs lead to clonal expansion of immune cell subsets, particularly effector CD8+ T cells and that primary or acquired failure to TCE therapy is associated with exhaustion of CD8+ T cells. Importantly, treatment failure or loss of response was not solely associated with immune-ME alterations but also MM intrinsic adaptations, such as loss of the target epitope and MHC class I protein.…”

Section: The Immune Microenvironment During Myeloma Therapy and In Re...mentioning

confidence: 99%

“…As seen in the previous studies, immune profiling differed between responders and nonresponders with higher granzyme B expression in CD8+ T cells of responders, suggesting treatment induced T‐cell activation with increased killing capacity. Friedrich et al determined the immunological single‐cell mechanisms of resistance to bispecific BCMAxCD3 T‐cell engager (TCE) therapy, a novel immunotherapy leading to unprecedented response rates in refractory MM 14 . They show that TCEs lead to clonal expansion of immune cell subsets, particularly effector CD8+ T cells and that primary or acquired failure to TCE therapy is associated with exhaustion of CD8+ T cells.…”

Section: The Immune Microenvironment During Myeloma Therapy and In Re...mentioning

confidence: 99%

The Immune Microenvironment in Multiple Myeloma Progression at a Single-cell Level

Schinke

Weinhold

2023

HemaSphere

Self Cite

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The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients

Cited by 110 publications

References 58 publications

Sequential Antigen-loss and Branching Evolution in Lymphoma after Anti-CD19 and Anti-CD20 Targeted T Cell Redirecting Immunotherapy

Sequential Antigen-loss and Branching Evolution in Lymphoma after Anti-CD19 and Anti-CD20 Targeted T Cell Redirecting Immunotherapy

T‐cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions

The Immune Microenvironment in Multiple Myeloma Progression at a Single-cell Level

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