Bone marrow expands the repertoire of functional T cells targeting tumor-associated antigens in patients with resectable non-small-cell lung cancer

Safi, Seyer; Yamauchi, Yoshikane; Stamova, Slava; Rathinasamy, Anchana; Winkel, Jan op den; Jünger, Simone; Bucur, Mariana; Umansky, Ludmilla; Warth, Arne; Herpel, Esther; Eichhorn, Martin; Winter, Hauke; Hoffmann, Hans; Beckhove, Philipp

doi:10.1080/2162402x.2019.1671762

Cited by 7 publications

(6 citation statements)

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“…Very few studies have made a comparison between the PB and BM immune cell repertoire in response to immunotherapies. 23,24 To our knowledge, this is the first report addressing the differential capacity of blinatumomab to modulate PB and BM immune landscapes.…”

Section: Discussionmentioning

confidence: 91%

“…As a consequence of this mode of action, it is not surprising that the changes occurring during and after blinatumomab treatment on immune cells collected from the PB may differ from those observed in the BM, where leukaemic cells mostly reside and grow. Very few studies have made a comparison between the PB and BM immune cell repertoire in response to immunotherapies 23,24 . To our knowledge, this is the first report addressing the differential capacity of blinatumomab to modulate PB and BM immune landscapes.…”

Section: Discussionmentioning

confidence: 92%

“…Indeed, it is well known that the immunological tumour microenvironment plays a crucial role in promoting tumour growth and progression and in affecting treatment efficacy. 23,24 The immune microenvironment is emerging as a hallmark for many haematological malignancies, including ALL. [25][26][27] However, a systematic and extensive characterization of the BM immune landscape correlated to the effects of immunotherapies is still lacking.…”

Section: Discussionmentioning

confidence: 99%

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Blinatumomab differentially modulates peripheral blood and bone marrow immune cell repertoire: A Campus ALL study

Ocadlikova,

Lussana,

Fracchiolla

et al. 2023

Br J Haematol

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SummaryBlinatumomab is the first bi‐specific T‐cell engager approved for relapsed or refractory B‐cell precursor acute lymphoblastic leukaemia (B‐ALL). Despite remarkable clinical results, the effects of blinatumomab on the host immune cell repertoire are not fully elucidated. In the present study, we characterized the peripheral blood (PB) and, for the first time, the bone marrow (BM) immune cell repertoire upon blinatumomab treatment. Twenty‐nine patients with B‐ALL received blinatumomab according to clinical practice. Deep multiparametric flow cytometry was used to characterize lymphoid subsets during the first treatment cycle. Blinatumomab induced a transient redistribution of PB effector T‐cell subsets and Treg cells with a persistent increase in cytotoxic NK cells, which was associated with a transient upregulation of immune checkpoint receptors on PB CD4 and CD8 T‐cell subpopulations and of CD39 expression on suppressive Treg cells. Of note, BM immune T‐cell subsets showed a broader post‐treatment subversion, including the modulation of markers associated with a T‐cell‐exhausted phenotype. In conclusion, our study indicates that blinatumomab differentially modulates the PB and BM immune cell repertoire, which may have relevant clinical implications in the therapeutic setting.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Blinatumomab differentially modulates peripheral blood and bone marrow immune cell repertoire: A Campus ALL study

Ocadlikova,

Lussana,

Fracchiolla

et al. 2023

Br J Haematol

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“…In solid cancer patients it cannot be excluded that BM T cells are actively engaged in micrometastasis control in this organ, even in the absence of evident metastases. BM tumor-specific T cells are functional, for example they produce IFNg and TNF-a (89,96), and in most cases they are not inhibited by Tregs in the organ (97,98). Considering that the BM represents a reservoir of functional memory T cells in tumor-bearing individuals, innovative anti-tumor T cell transfer approaches exploiting the BM as a source of T cells have been proposed (99)(100)(101).…”

Section: Recirculating Memory T Cellsmentioning

confidence: 99%

The Emerging Interplay Between Recirculating and Tissue-Resident Memory T Cells in Cancer Immunity: Lessons Learned From PD-1/PD-L1 Blockade Therapy and Remaining Gaps

et al. 2021

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Remarkable progress has been made in the field of anti-tumor immunity, nevertheless many questions are still open. Thus, even though memory T cells have been implicated in long-term anti-tumor protection, particularly in prevention of cancer recurrence, the bases of their variable effectiveness in tumor patients are poorly understood. Two types of memory T cells have been described according to their traffic pathways: recirculating and tissue-resident memory T cells. Recirculating tumor-specific memory T cells are found in the cell infiltrate of solid tumors, in the lymph and in the peripheral blood, and they constantly migrate in and out of lymph nodes, spleen, and bone marrow. Tissue-resident tumor-specific memory T cells (TRM) permanently reside in the tumor, providing local protection.Anti-PD-1/PD-L1, a type of immune checkpoint blockade (ICB) therapy, can considerably re-invigorate T cell response and lead to successful tumor control, even in patients at advanced stages. Indeed, ICB has led to unprecedented successes against many types of cancers, starting a ground-breaking revolution in tumor therapy. Unfortunately, not all patients are responsive to such treatment, thus further improvements are urgently needed. The mechanisms underlying resistance to ICB are still largely unknown. A better knowledge of the dynamics of the immune response driven by the two types of memory T cells before and after anti-PD-1/PD-L1 would provide important insights on the variability of the outcomes. This would be instrumental to design new treatments to overcome resistance.Here we provide an overview of T cell contribution to immunity against solid tumors, focusing on memory T cells. We summarize recent evidence on the involvement of recirculating memory T cells and TRM in anti-PD-1/PD-L1-elicited antitumor immunity, outline the open questions in the field, and propose that a synergic action of the two types of memory T cells is required to achieve a full response. We argue that a T-centric vision focused on the specific roles and the possible interplay between TRM and recirculating memory T cells will lead to a better understanding of anti-PD-1/PD-L1 mechanism of action, and provide new tools for improving ICB therapeutic strategy.

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“…In patients with multiple myeloma and other hematological malignancies that relapse post-transplant, MILs have been shown to contain tumor antigen-specific T cells and adoptive cell therapy (ACT) using MILs has demonstrated antitumor activity. 2 3 The bone marrow has been shown to harbor tumor-antigen specific T cells in patients with melanoma, 4 5 glioblastoma, 6 breast, 7 non-small-cell lung 8 and pancreatic cancers. 9 Here, we sought to determine if tumor-specific MILs could be expanded from the bone marrow of patients with a range of different solid tumors.…”

mentioning

confidence: 99%

154 Marrow-infiltrating lymphocytes (MILs): A novel adoptive immunotherapy for hematological and solid tumors

Rudraraju¹,

DeOliveira²,

Seiz³

et al. 2020

Regular and Young Investigator Award Abstracts

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BackgroundMarrow infiltrating lymphocytes (MILsTM) are the product of activating and expanding bone marrow T cells.1 The bone marrow is a specialized niche in the immune system enriched for antigen-experienced, memory T cells. In patients with multiple myeloma and other hematological malignancies that relapse post-transplant, MILs have been shown to contain tumor antigen-specific T cells and adoptive cell therapy (ACT) using MILs has demonstrated antitumor activity.2 3 The bone marrow has been shown to harbor tumor-antigen specific T cells in patients with melanoma,4 5 glioblastoma,6 breast,7 non-small-cell lung8 and pancreatic cancers.9 Here, we sought to determine if tumor-specific MILs could be expanded from the bone marrow of patients with a range of different solid tumors.MethodsBone marrow and blood samples were collected from patients with advanced and metastatic cancers. To date, samples have been collected from a minimum of four patients with non-small cell lung cancer (NSCLC), prostate cancer, head and neck cancer, glioblastoma, and breast cancer. Samples from patients with multiple myeloma were used as a reference control. Utilizing a 10-day proprietary process, MILs and peripheral blood lymphocytes (PBLs) were activated and expanded from patient bone marrow and blood samples, respectively. T cell lineage-specific markers (CD3, CD4 and CD8) were characterized by flow cytometry pre- and post-expansion.Tumor-specific T cells were quantitated in expanded MILs and PBLs using a previously described cytokine-secretion assay [2]. Briefly, autologous antigen-presenting cells (APCs) were pulsed with lysates from allogeneic cancer cell lines and co-cultured with activated MILs or PBLs. APCs pulsed with irrelevant mis-matched cancer cell line lysates or media alone were used as negative controls. Tumor-specific T cells were defined as the IFNgamma-producing population by flow cytometry.ResultsMILs were successfully expanded from all patient bone marrow samples tested, regardless of tumor type. Cytokine-producing tumor-specific CD4+ and CD8+ T cells were detected in each of the expanded MILs. In contrast, tumor-specific T cells were not detected in any of the matched activated and expanded PBLs.ConclusionsMILs have been successfully grown for all solid tumor types evaluated, including NSCLC, prostate, head and neck, glioblastoma and breast cancer. Clinical studies have been completed in patients with multiple myeloma and other hematological cancers. 2 3 A phase IIa trial to evaluate MILs in combination with a checkpoint inhibitor is underway in patients with anti-PD1/PDL1-refractory NSCLC (ClinicalTrials.gov Identifier: NCT04069936). The preclinical data presented herein demonstrate that expanding MILs is feasible. MILs-based therapies hold therapeutic promise across a wide range of tumor indications.Ethics ApprovalThis study was approved by each participating instituion’s IRB.ReferencesBorrello I and Noonan KA. Marrow-Infiltrating Lymphocytes - Role in Biology and Cancer Therapy. Front Immunol 2016 March 30; 7(112)Noonan KA, Huff CA, Davis J, et al. Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci. Transl. Med 2015;7:288ra78.Biavati L, Noonan K, Luznik L, Borrello I. Activated allogeneic donor-derived marrow-infiltrating lymphocytes display measurable in vitro antitumor activity. J Immunother 2019 Apr;42(3):73–80.Müller-Berghaus J, Ehlert K, Ugurel S, et al. Melanoma-reactive T cells in the bone marrow of melanoma patients: association with disease stage and disease duration. Cancer Res 2006;66(12):5997–6001.Letsch A, Keilholz U, Assfalg G, et al., Bone marrow contains melanoma-reactive CD8+ effector T Cells and, compared with peripheral blood, enriched numbers of melanoma-reactive CD8+ memory T cells. Cancer Res 2003 Sep 1;63(17):5582–5586.Chongsathidkiet P, Jackson C, Koyama S, et al., Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nature Medicine 2018 Aug 13; 24:1459–1468.Feuerer M, Rocha M, Bai L, et al. Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients. Int J Cancer 2001; 92(1):96–105.Safi S, Yamauchi Y, Stamova S, et al. Bone marrow expands the repertoire of functional T cells targeting tumor-associated antigens in patients with resectable non-small-cell lung cancer. Oncoimmunology 2019;8(12):e1671762.Schmitz-Winnenthal FH, Volk C, Z’Graggen K, et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 2005;65(21):10079–87.

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Bone marrow expands the repertoire of functional T cells targeting tumor-associated antigens in patients with resectable non-small-cell lung cancer

Cited by 7 publications

References 47 publications

Blinatumomab differentially modulates peripheral blood and bone marrow immune cell repertoire: A Campus ALL study

Blinatumomab differentially modulates peripheral blood and bone marrow immune cell repertoire: A Campus ALL study

The Emerging Interplay Between Recirculating and Tissue-Resident Memory T Cells in Cancer Immunity: Lessons Learned From PD-1/PD-L1 Blockade Therapy and Remaining Gaps

154 Marrow-infiltrating lymphocytes (MILs): A novel adoptive immunotherapy for hematological and solid tumors

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