Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study

Querfeld, Christiane; Thompson, John A.; Taylor, Matthew H.; DeSimone, Jennifer; Zain, Jasmine; Shustov, Andrei R.; Johns, Carolyn; McCann, Sue; Lin, Gloria H. Y.; Petrova, Penka S.; Uger, Robert A.; Molloy, Naomi; Shou, Yaping; Akilov, Oleg E.

doi:10.1016/s2352-3026(21)00271-4

Cited by 49 publications

(39 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We compared the CAILs 2 months after the treatment in 11 patients, with 7 patients in the monotherapy cohort (anti-CD47 only) vs. 4 patients in the combination cohort. The overall response rate was 27.2% in the monotherapy cohort (which is in accordance with our published data on a larger cohort of patients [ 36 ]) vs. 75% in the combination cohort. Rapid skin clearance was observed within the first 3–4 weeks of a combination therapy with TTI-621 and pegylated IFN-α2a ( Figure 6 c) in all four patients and was accompanied by an increase of NK cells (CD3-CD16-CD56 bright ) in the peripheral blood ( Figure 6 b) and in TME ( Figure 6 d).…”

Section: Resultssupporting

confidence: 90%

“…Disruption of the CD47-SIRPα signaling axis results in the enhanced phagocytosis of both solid [ 39 ] and hematopoietic tumor cells [ 40 ], leading to significant anti-tumor activity in vivo [ 41 ]. The results of phase I clinical trials clearly demonstrated that anti-CD47 blockade enhances antitumor immunity and leads to clinical response in CTCL patients [ 33 , 36 ]. Overriding CD47 while supplementing with FDA-approved IFNα that stimulates cytotoxic cells unleashes tumor clearance.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical Response to Anti-CD47 Immunotherapy Is Associated with Rapid Reduction of Exhausted Bystander CD4+ BTLA+ T Cells in Tumor Microenvironment of Mycosis Fungoides

Jiang

Kruglov

Lin

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

Cancer progression in mycosis fungoides, the most common form of cutaneous T-cell lymphoma, occurs in a predictable, sequential pattern that starts from patches and that evolves to plaques and later to tumors. Therefore, unlocking the relationship between the microarchitecture of mycosis fungoides and the clinical counterparts of that microstructure represents important steps for the design of targeted therapies. Using multispectral fluorescent imaging, we show that the progression of mycosis fungoides from plaque to tumor parallels the cutaneous expansion of the malignant CD4+ T cells that express TOX. The density of exhausted BTLA+ CD4+ T cells around malignant CD4+TOX+ cells was higher in tumors than it was in plaques, suggesting that undesired safeguards are in place within the tumor microenvironment that prevent immune activation and subsequent cancer eradication. Overriding the CD47 checkpoint with an intralesional SIRPαFc fusion decoy receptor induced the resolution of mycosis fungoides in patients that paralleled an amplified expansion of NK and CD8+ T cells in addition to a reduction of the exhausted BTLA+ CD4+ T cells that were engaged in promiscuous intercellular interactions. These therapeutic benefits of the CD47 blockade were further unleashed by adjuvant interferon-α, which stimulates cytotoxic cells, underscoring the importance of an inflamed microenvironment in facilitating the response to immunotherapy. Collectively, these findings support CD47 as a therapeutic target in treating mycosis fungoides and demonstrate a synergistic role of interferon-α in exploiting these clinical benefits.

show abstract

Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Clinical Response to Anti-CD47 Immunotherapy Is Associated with Rapid Reduction of Exhausted Bystander CD4+ BTLA+ T Cells in Tumor Microenvironment of Mycosis Fungoides

Jiang

Kruglov

Lin

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…TTI-621 monotherapy resulted in an ORR of 20, 13 and 5% in patients with T cell NHL, HL and AML, respectively [ 211 ]. Following these results, 35 patients with cutaneous T cell lymphomas (CTCL) or solid tumors received intralesional TTI-621 in another phase I trial (NCT02890368) [ 212 ]. Treatment was well tolerated, as no treatment related adverse events of grade III or higher were observed.…”

Section: Targeting Cd47-sirpα To Potentiate Antibody Therapymentioning

confidence: 99%

“…Treatment was well tolerated, as no treatment related adverse events of grade III or higher were observed. Rapid responses (median 45 days) were observed and 90% of patients had reduced tumor sizes after treatment with TTI-621 [ 212 ]. Thus, these initial phase I trials demonstrate that treatment with TTI-621 does not cause severe toxicities (at the MTD) and has some anti-tumor effects in various cancer types, e.g., CTCL and hematologic cancers.…”

Section: Targeting Cd47-sirpα To Potentiate Antibody Therapymentioning

confidence: 99%

Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils

Behrens

Berg

Egmond

2022

Cancers

View full text Add to dashboard Cite

In the past 25 years, a considerable number of therapeutic monoclonal antibodies (mAb) against a variety of tumor-associated antigens (TAA) have become available for the targeted treatment of hematologic and solid cancers. Such antibodies opsonize cancer cells and can trigger cytotoxic responses mediated by Fc-receptor expressing immune cells in the tumor microenvironment (TME). Although frequently ignored, neutrophils, which are abundantly present in the circulation and many cancers, have demonstrated to constitute bona fide effector cells for antibody-mediated tumor elimination in vivo. It has now also been established that neutrophils exert a unique mechanism of cytotoxicity towards antibody-opsonized tumor cells, known as trogoptosis, which involves Fc-receptor (FcR)-mediated trogocytosis of cancer cell plasma membrane leading to a lytic/necrotic type of cell death. However, neutrophils prominently express the myeloid inhibitory receptor SIRPα, which upon interaction with the ‘don’t eat me’ signal CD47 on cancer cells, limits cytotoxicity, forming a mechanism of resistance towards anti-cancer antibody therapeutics. In fact, tumor cells often overexpress CD47, thereby even more strongly restricting neutrophil-mediated tumor killing. Blocking the CD47-SIRPα interaction may therefore potentiate neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) towards cancer cells, and various inhibitors of the CD47-SIRPα axis are now in clinical studies. Here, we review the role of neutrophils in antibody therapy in cancer and their regulation by the CD47-SIRPα innate immune checkpoint. Moreover, initial results of CD47-SIRPα blockade in clinical trials are discussed.

show abstract

“…In recent years, multiple reagents targeting the CD47-SIRPα axis raised and showed a remarkable antitumor efficacy in multiple solid tumors, some of which were already at the phase I study, supporting the essential effect of regulating the CD47-SIRPα signal in cancer immunotherapy ( 28 , 41 , 42 ). Previously, we determined the antitumor efficacy of SIRPαFc fusion protein and found that SIRPαFc elicited potent macrophage-mediated antitumor efficacy in NSCLC via blocking endogenous CD47-SIRPα phagocytosis-suppressive signals and inducing antitumor phagocytosis ( 21 ).…”

Section: Discussionmentioning

confidence: 92%

A SIRPαFc Fusion Protein Conjugated With the Collagen-Binding Domain for Targeted Immunotherapy of Non-Small Cell Lung Cancer

Liu

Meng

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

The SIRPαFc fusion protein can block the immunosuppressive CD47-SIRPα signal between macrophages and tumor cells as a decoy receptor and has demonstrated its immunotherapeutic efficacy in various tumors. However, its clinical application was limited because of the potential hematologic toxicity. The heptapeptide “TKKTLRT” is a collagen-binding domain (CBD) which can bind collagen specifically. Herein, we aim to improve the tumor targeting of SIRPαFc and therefore avoid its unnecessary exposure to normal cells through synthesizing a TKKTLRT–SIRPαFc conjugate. Experiments at molecular and cellular levels indicate that the TKKTLRT–SIRPαFc conjugate-derived collagen-binding affinity and the introduction of CBD did not impact the CD47-binding affinity as well as its phagocytosis-promoting effect on NSCLC cells. In vivo distribution experiments showed that CBD–SIRPαFc accumulated in tumor tissue more effectively compared to unmodified SIRPαFc, probably due to the exposed collagen in the tumor vascular endothelium and stroma resulting from the abnormal vessel structure. On an A549 NSCLC nude mouse xenograft model, CBD–SIRPαFc presented more stable and effective antitumor efficacy than SIRPαFc, along with significantly increased CD11b+F4/80+ macrophages especially MHC II+ M1 macrophages within tumors. All of these results revealed that CBD brought a tumor-targeting ability to the SIRPαFc fusion protein, which contributed to the enhanced antitumor immune response. Altogether, the CBD–SIRPαFc conjugate may have the potential to be an effective tumor immunotherapy with improved antitumor efficacy but less non-tumor-targeted side effect.

show abstract

Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study

Cited by 49 publications

References 26 publications

Clinical Response to Anti-CD47 Immunotherapy Is Associated with Rapid Reduction of Exhausted Bystander CD4+ BTLA+ T Cells in Tumor Microenvironment of Mycosis Fungoides

Clinical Response to Anti-CD47 Immunotherapy Is Associated with Rapid Reduction of Exhausted Bystander CD4+ BTLA+ T Cells in Tumor Microenvironment of Mycosis Fungoides

Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils

A SIRPαFc Fusion Protein Conjugated With the Collagen-Binding Domain for Targeted Immunotherapy of Non-Small Cell Lung Cancer

Contact Info

Product

Resources

About