Background

ICT01, an anti-BTN3A targeted mAb that selectively activates γ9δ2 T cells, is being studied in the ongoing phase 1/2a EVICTION Trial in advanced solid and hematologic cancers (NCT04243499). ICT01-activated γ9δ2 T cells are known to kill acute myeloid leukemia blasts and lymphoma cell lines both in vitro and in vivo, making γ9δ2 T cells of interest as a novel immunotherapeutic strategy against hematologic cancers. Here we present data from the EVICTION phase 1 in relapsed/refractory hematological cancers.

Methods

Patients with hematologic cancers who failed available standard of care received IV ICT01 alone (200 μg to 75 mg) every 21 days. Antitumor assessment by imaging or bone marrow analysis was done every 8 weeks after using the Response Evaluation Criteria in Lymphoma (RECIL) and IWG Criteria for AML. Safety reviews were conducted prior to dose escalation. Disease Control Rate (DCR) was the primary efficacy endpoint and defined as the sum of complete response (CR), CR with incomplete recovery (CRi), partial response (PR) and stable disease (SD). Blood samples were collected for pharmacokinetic and pharmacodynamic analyses.

Results

Dose escalation was completed with 26 patients (1 Diffuse Large B-cell Lymphoma, 1 Follicular Lymphoma, 24 AML), with no dose-limiting toxicities and a good safety profile similar to that in solid tumors. First-dose infusion-related reaction, nausea, fever and vomiting (Grade 1/2) were the most common treatment-related AEs. Only 2 Grade 3 events of neutropenia were reported and resolved with continued treatment. Target occupancy on circulating T cells ≥ 30% was observed 30 min post doses ≥ 700 μg, with activation and migration of >95% γ9δ2 T cells from the blood within 24hrs of dosing. Ten of 26 patients were evaluable at week 8 with an observed DCR of 30%. One DLBCL patient still receiving ICT01 at 7 mg has had a PR from Wk 40 to Wk 94/C32. In the 20 mg dose group, two AML patients achieved stable disease at week 8 with one still on study at Wk 53/C19.

Conclusions

The good safety profile and encouraging clinical activity data in these last-line patients support further testing of ICT01 in a first-line AML phase 2a expansion cohort in combination with VEN/AZA in EVICTION that will start mid-2023.

Clinical trial identification

EudraCT 2019-003847-31; NCT04243499.

Legal entity responsible for the study

ImCheck Therapeutics.

Funding

ImCheck Therapeutics.

Disclosure

S. Garciaz: Financial Interests, Personal, Advisory Role: AbbVie, Astellas, Novartis, Amgen. S. Champiat: Financial Interests, Personal, Invited Speaker: Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Genmab, Janssen, Merck, Merck Serono, Novartis and Roche; Financial Interests, Personal, Other, Principal Investigator of Clinical Trials: AbbVie, Amgen, Boehringer Ingelheim, Cytovation, Eisai, Imcheck Therapeutics, Molecular Partners Ag, Merck, Ose Pharma, Pierre Fabre, Sanofi Aventis, SOTIO A.S, Transgene; Financial Interests, Personal, Advisory Board: Alderaan Biotechnology, Amgen, AstraZeneca, Avacta, Celanese, Domain Therapeutics, Ellipses Pharma, Genmab, Immunicom, Inc., Nanobiotix, Nextcure, Oncovita, Pierre Fabre, Seagen, Tatum Bioscience, Tollys SAS, UltraHuman8; Financial Interests, Personal, Other, Travel and congress: Amgen, AstraZeneca, Bristol Myers Squibb, Merck, Ose Pharma, Roche, SOTIO; Financial Interests, Institutional, Other, As part of the Drug Development Department (DITEP)=Principal/sub-Investigator of Clinical Trials: Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Adaptimmune, AdlaiAstex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, BicycleTx Ltd., Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevac, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd., Forma Tharapeutics, Gamamabs, Genentech, GSK, H3 Biomedicine, F. Hoffmann-La Roche AG, Imcheck Therapeutics, Incyte Corporation, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Genomics, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre Medicament, Relay Therapeutics, Inc., Roche, Sanofi Aventis, Seattle Genetics, SOTIO A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Transgene S.A, Turning Point Therapeutics, Xencor; Financial Interests, Institutional, Research Grant, As part of the Drug Development Department (DITEP) =Research Grants: AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Pfizer, Roche, Sanofi; Non-Financial Interests, Institutional, Product Samples, As part of the Drug Development Department (DITEP) =Non-financial support (drug supplied): AstraZeneca, BMS, Boehringer Ingelheim, GSK, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. K. Lemmens, A. de Gassart, P. Brune, E. Valentin, P.A. Frohna: Financial Interests, Personal, Full or part-time Employment: ImCheck Therapeutics. D. Olive: Financial Interests, Personal, Advisory Board, Shareholder: ImCheck Therapeutics. All other authors have declared no conflicts of interest.

Background

SAR’579, a trifunctional anti-CD123 NKp46×CD16 NKCE, enabling a cytolytic synapse between natural killer (NK) cells and CD123+ tumor cells leading to NK cell activation and tumor cell killing. We report preliminary PK/PD of SAR’579 from a phase 1/2 trial in pts with R/R AML, B-ALL or HR-MDS (EudraCT 2021-004287-98 Apr 26, 2023/NCT05086315).

Methods

SAR’579 was administered IV twice weekly or once weekly (QW) per dose level (DL) in first 2 weeks of cycle 1 and QW for rest of induction cycles. Peripheral blood (to measure plasma concentrations and immunogenicity assessment) and bone marrow samples were collected for PK/PD analysis during each induction cycle. Analysis of cytokines, as potential safety and PD markers, including IL-6, TNFα and IFNγ, was performed using Meso Scale Discovery®.

Results

From Dec 14, 2021, to Oct 17, 2022, 19 pts were treated across 5 DLs (3 in DL1 and 4 each in DL2 to DL5) between 10-3000 μg/kg/dose. No dose limiting toxicities were observed. At 1000 μg/kg QW, 3/8 pts achieved complete remission (CR) (2 CR/1 incomplete hematologic recovery). Early immunogenicity was 26% with no impact on safety/efficacy. Post first administration of SAR’579, circulating maximum (max) concentration increased with dose increase with a supra-dose proportionality between DL1 and DL5. PK linearity was achieved at 3000 μg/kg QW (DL5) at the end of cycle 1. Table: 823O

Median (max) peak cytokine concentrations (pg/mL) observed during DL1-5

Conclusions

SAR’579 was well tolerated till 3000 μg/kg QW with clinical benefit in pts with R/R AML. Observed peak cytokine levels did not show significant dose-related increase and no association between elevated peak cytokine levels and clinical responses. The results are consistent with the improved safety profile compared to CD123-targeted T-cell engagers.

Clinical trial identification

EudraCT 2021-004287-98, 26 April 2023; NCT05086315.

Editorial acknowledgement

Deepshikha Khurana, Sanofi Global Hub.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

A. Bajel: Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Other, Honoraria: Amgen, AbbVie, Pfizer, Astellas, Novartis. A. Maiti: Financial Interests, Personal and Institutional, Research Funding: Celgene, Lin BioScience. S. Fleming: Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other, Honoraria: Novartis, Bristol Myers Squibb, Pfizer; Financial Interests, Personal, Advisory Role, Honoraria: Amgen; Financial Interests, Personal, Advisory Role: Novartis, Bristol Myers Squibb, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Amgen, Pfizer; Financial Interests, Personal and Institutional, Research Funding: Amgen. S. De Button: Financial Interests, Personal and Institutional, Research Funding: Agios, Forma Therapeutics; Financial Interests, Personal, Other, Honoraria: AbbVie, Celgene, Jazz Pharmaceuticals, Novartis, Pfizer, Astellas Pharma a/s Nordic Operations. K. Jensen, S. Ziti-Ljajic, D. Draganov, F. Rotolo, C. Palu, J. Courta, W. Passe-Coutrin, K. Traudtner, T. Wagenaar, G. Abbadessa: Financial Interests, Personal, Stocks/Shares, Employed by Sanofi and may hold stock and/or stock options: Sanofi. A. Selwyn Stein: Financial Interests, Personal, Speaker’s Bureau: Amgen. All other authors have declared no conflicts of interest.

Background

Despite the generally favorable prognosis of POAML, There is limited understanding of the extent to which primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (POAML) impacts a patient’s risk of death and how different treatment managements affect prognosis and toxicities in this specific MALT site.

Methods

This study analyzed major long-term outcomes of patients with POAML lymphoma and the prognostic significance of baseline clinical features. We reviewed the clinical features, treatments, disease course and long-term outcome of 262 patients with Ann-Arbor stage IE POAML diagnosed between 2000 to 2012. Outcomes were analyzed using crude overall survival (OS) and relative survival (RS) by standardized mortality ratio (SMR). A cross-sectional study was conducted using OSDI questionnaires to evaluate the long-term ocular adverse effects.

Results

The median age was 55 years. With a median follow-up of 66 month, the 5-year OS, lymphoma-specific mortality and competing non-lymphoma mortality were 96.8%, 0.4% and 2.3%, respectively, and the estimated 10-year corresponding rates were 90.0%, 0.4% and 4.2%; the overall SMR was 1.02 (95% confidence interval [CI]: 0.60-1.61, P = 0.963). The OS and RS rates were similar across the treatment groups; however, RT associated with significantly decreased risks of failure (11.0%, n = 82, p = 0.006), compared to observation (33.3%, n = 81), surgery (28.6%, n = 70), and CT/IT groups (24.1%, n = 29). The cross-sectional study indicated that RT wasn’t obviously increased the intermediate-severe grades of dry eye diseases for a relative long-time after treatment.

Conclusions

Overall, a diagnosis of stage IE POAML lymphoma had similar long-term survival to the general population. RT associated with lower failure rates and minor ocular adverse effects.

Legal entity responsible for the study

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The use of immune checkpoint inhibitors has revolutionized the treatment of solid tumors and hematologic malignancies, clinical evidence has demonstrated anti-PD-1 therapy to be effective tools in PTCL. However, factors that may influence primary sensitivity or resistance to anti-PD-1 therapy in PTCL, such as TMB and genomic alterations, have not yet been clarified.

Methods

We enrolled 89 peripheral T cell lymphoma (PTCL) patients in phase II clinical trial of geptanolimab and performed targeted next-generation sequencing for 440 cancer-associated genes. Clinical data were collected and correlated with genetic mutations. In vitro, studies were conducted to evaluate the effect of JAK3 mutations on PD-L1 expression.

Results

PD-L1 expression was significantly elevated in complete response (CR)/ partial response (PR) patients compared to progressive disease (PD) patients, while tumor mutation burden (TMB) didn’t exhibit significant prognostic value which may be confounded by the variation across PTCL subtypes. The most frequent mutations occurred in TP53, KMT2C, KMT2D, JA3, LRP1B, and SETD2. Shorter time to death was related to mutations in SETD2 (HR=5.73, P=0.0135) or KME2D (HR=3.17, P=0.0533). Shorter PFS was correlated with JAK3 mutations (HR=5.97, P=0.0144). The subset PTCL patients (86.4%) with enrichment of non-APOBEC-related mutation signature had higher TMB level (P=0.076) and superior PFS (P=0.031) to non-APOBEC-enriched samples. In vitro experiments revealed JAK3 A573V, M511I, and E958K mutations led to lower PD-L1 expression through downregulated of the expression of PI3K and MAPK.

Conclusions

In this study we comprehensively depicted the pre-treatment mutation profiles of PTCL and identified genetic alterations with prognostic value for anti-PD-1 therapy. Notably, we found JAK3 mutations which are vital and prevalent in PTCL reduced PD-L1 levels in vivo and in vitro, which are of great clinical and biological sense.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The current standard of care for extranodal NK/T cell lymphoma (ENKTL) is L-asparaginase or pegaspargase-based multiagent chemotherapy combined with radiotherapy. However, overall survival was significantly lower in those patients with inadequate response to L-asparaginase-based multiagent chemotherapy.

Methods

In this prospective, single-arm, multicenter, phase II clinical study, patients with stage I/II ENKTL who did not achieve CR after 2-3 cycles of multiagent chemotherapy containing L-asparaginase or pegaspargase were enrolled. Patients received toripalimab (240 mg, d1, Q3w) plus radiotherapy (95% PTV 56 Gy/28f, d1-d5/w), sequentially with or without 2 to 4 cycles chemotherapy. Then patients received toripalimab for 1 year or until disease progression or intolerable toxicity. The primary endpoint was CR rate.

Results

From February 2019 to present, 22 patients were enrolled who have received the response assessment at least once after radiotherapy. All were originated from the upper aerodigestive tract with a median age of 45 years (range 26-64). 14 were male. 17 (77.3%) and 5 (22.7%) patients were Lugano stage I and II, respectively; 81% were primary tumor invasion (PTI). 8/22 patients (36.4%) had PR, 8/22 had (36.4%) SD, 6/22 (27.2) had PD after previous 2-3 cycles chemotherapy. All patients completed the radiotherapy. The ORR was 90.9%, including 17 CR (77.3%), 3 PR (13.6%), 2 PD (9.1%). 8 patients who responded to previous chemotherapy continued 2 cycles of chemotherapy after completion of radiotherapy. Others received toripalimab alone (median dose: 11; range 3-17). Up to date, the median follow-up time was 23 months (range 3-78), the 2-year PFS rate was 81.6%, and all patients survived. The main adverse events during and after radiotherapy were oral mucositis and hypothyroidism. No grade 3 or higher toxicity occurred.

Conclusions

Toripalimab combined with radiotherapy is safe and have promising efficacy for stage I/II ENKTL who have poor response after previous standard chemotherapy.

Clinical trial identification

ChiCTR2100045147.

Editorial acknowledgement

We acknowledge Shanghai Junshi Bioscience for supplying the study drug.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.