Summary
Background
Effective treatment options are scarce for relapsed or refractory T-cell lymphoma. This study assesses the safety and activity of CTX130 (volamcabtagene durzigedleucel), a CD70-directed, allogeneic chimeric antigen receptor (CAR) immunotherapy manufactured from healthy donor T cells, in patients with relapsed or refractory T-cell lymphoma.
Methods
This single-arm, open-label, phase 1 study was done at ten medical centres across the USA, Australia, and Canada in patients (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma or cutaneous T-cell lymphoma, who had received at least one or at least two previous systemic therapy lines, respectively, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. Patients underwent lymphodepletion with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 (intravenously daily for 3 days), followed by intravenous CTX130 infusion at dose levels ranging from 3 × 107 CAR+ T cells (dose level 1) to 9 × 108 CAR+ T cells (dose level 4). The primary endpoint was the incidence of adverse events, defined as dose-limiting toxicities occurring within 28 days post-infusion. Secondary endpoints included objective response rate. Safety and activity analyses were performed on data from all patients who received CTX130. The trial is registered with ClinicalTrials.gov (NCT04502446) and EudraCT (2019-004526-25) and is closed to enrolment.
Findings
Between Aug 28, 2020, and May 30, 2023, 41 patients were enrolled and 39 (95%) received CTX130. The median patient follow-up was 7.4 months (IQR 3.1–12.2). 21 (54%) of 39 patients were female and 18 (46%) were male. 24 (62%) patients were White, eight (21%) were Black, three (8%) were Asian, three (8%) were from other racial or ethnic groups, and one (3%) was not reported. The median number of previous lines of anticancer therapy was 2.5 (IQR 1.3–4.0) for patients with peripheral T-cell lymphoma and 5.0 (IQR 5.0–7.0) for patients with cutaneous T-cell lymphoma. Cytokine release syndrome was the most common adverse event, occurring in 26 (67%) of 39 patients (23 were grade 1–2, two were grade 3, and one was a grade 4 dose-limiting toxicity at dose level 4). Grade 1–2 neurotoxic events were observed in four (10%) of 39 patients. The most common grade 3–4 adverse events were neutropenia (14 [36%]), anaemia (11 [28%]), and thrombocytopenia (six [15%]). Serious adverse events occurred in 25 (64%) patients, with CTX130-related serious adverse events in 14 (36%) patients, the most common related serious adverse event being cytokine release syndrome in 11 (28%) patients. 21 patients died, 16 from progressive disease and five from adverse events considered unrelated to CTX130 treatment. 18 of 39 patients (46.2% [95% CI 30.1–62.8) had an objective response. Of those treated at dose level 3 and higher, 16 of 31 patients (51.6% [33.1–69.8]) had objective responses, including six (19.4% [7.5–37.5]) with complete response and ten (32.3% [16.7–51.4]) with a partial response.
Interpretation
In patients with heavily pretreated T-cell lymphoma, CTX130 showed manageable safety and a promising objective response rate. This study shows that allogeneic, readily available CAR T cells can be safely given to patients with relapsed or refractory T-cell lymphoma. A next-generation CAR T-cell therapy containing additional potency gene edits (CTX131) is in clinical development.
Introduction
Mature T-cell lymphomas represent approximately 15% of non-Hodgkin lymphomas and consist of two broad clinical subtypes: cutaneous T-cell lymphoma and peripheral T-cell lymphoma. About 2800 cases of cutaneous T-cell lymphoma are diagnosed in the USA annually.1 The most common subtype is mycosis fungoides, characterised by skin involvement with variable lymph node, blood, and visceral involvement. Sézary syndrome is an erythrodermic subtype distinguished by leukaemic disease. Approximately 5000 cases of peripheral T-cell lymphoma are diagnosed in the USA annually.2 The three major nodal subtypes include peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large-cell lymphoma. Adult T-cell leukaemia or lymphoma is a rare T-cell lymphoma associated with human T-lymphotropic virus 1 infection that typically presents with high burden of leukaemic disease. Relapsed or refractory T-cell lymphomas have poor survival outcomes with current treatment regimens. The 5-year survival for advanced mycosis fungoides or Sézary syndrome is 52%3 and 38–70% for relapsed or refractory peripheral T-cell lymphoma,4,5 and the 4-year survival for acute and lymphoma subtypes of adult T-cell leukaemia or lymphoma is 11–16%.6
CD70 is a promising target in haematological malignancies and solid tumours due to its transient expression in activated lymphocytes and high expression on tumour cells.7 CD70-positivity rates (≥10% by immunohistochemistry) of 88% have been reported in cutaneous T-cell lymphoma and 59% in peripheral T-cell lymphoma.7 It has been proposed that CD70 suppresses the immune activity of infiltrating T cells during lymphomagenesis, in which tumours exploit the CD70–CD27 system to exhaust tumour-reactive T cells.8 Cusatuzumab (ARGX-110), a monoclonal antibody targeting CD70, was evaluated in patients with cutaneous T-cell lymphoma and led to an objective response rate of 23% (six of 26 patients) and no adverse events due to off-tumour CD70 targeting.9 Additionally, a preclinical study found that an antibody–drug conjugate targeting CD70 (SGN-CD70a) can reduce tumours in xenograft mouse models.10
CTX130 (volamcabtagene durzigedleucel) is a CD70-directed, allogeneic, chimeric antigen receptor (CAR) immunotherapy derived from healthy donor T cells. Targeted disruptions mediated by CRISPR-Cas9 include edits at the T-cell receptor α constant (TRAC) region to reduce T-cell receptor surface expression to avoid graft versus host disease. β2-microglobulin knockout reduces MHC class I expression to decrease the probability of host rejection, and CD70 knockout reduces target-driven fratricide (appendix p 13). CTX130 was previously investigated in a first-in-human study in adults with clear cell renal cell carcinoma with a disease control rate of 81.3% (13 of 16 patients), with grade 1–2 cytokine release syndrome reported in eight (50%) of 16 patients and no events of immune effector cell-associated neurotoxicity syndrome.11
In this study, we aimed to investigate the safety, activity, and cellular pharmacokinetics of CTX130 in patients with relapsed or refractory T-cell lymphoma.
Methods
Study design and participants
This single-arm, open-label, phase 1 study was conducted at ten medical centres across the USA, Australia, and Canada (appendix p 22), according to the Declaration of Helsinki. The protocol and all subsequent amendments were approved by local ethics committees or institutional review boards per country-specific requirements. Participants provided written, informed consent before enrolment. This study was registered with ClinicalTrials.gov (NCT04502446), and EudraCT (2019-004526-25), and is closed to enrolment.
Eligible patients were aged 18 years or older with relapsed or refractory peripheral T-cell lymphoma (ie, peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, or leukaemic and lymphomatous subtypes of adult T-cell leukaemia or lymphoma) or cutaneous T-cell lymphoma (ie, mycosis fungoides or Sézary syndrome [stage ≥IIB with disease involving two or more compartments or single-compartment disease with large-cell transformation]) who had received previous lines of systemic therapy (≥1 in patients with peripheral T-cell lymphoma or ≥2 in patients with cutaneous T-cell lymphoma); an Eastern Cooperative Oncology Group (ECOG) performance score of 0–1; adequate organ function; and measurable disease per modified Severity-Weighted Assessment Tool (mSWAT) score or peripheral blood tumour burden, or at least one measurable lesion by imaging (PET-CT or CT) per Lugano criteria.12 Patients with anaplastic large-cell lymphoma must have relapsed after brentuximab vedotin in a previous therapy line (or after ≥2 previous therapy lines if anaplastic lymphoma kinase positive). Exclusion criteria included previous allogeneic stem-cell transplantation and active CNS manifestation of underlying disease (appendix pp 2–4). The protocol was amended after enrolment of 36 patients (Nov 8, 2022) to include patients testing CD70 negative in tumour cells, in addition to those testing CD70 positive (≥10% by immunohistochemical analysis), to explore the association between CD70 expression and activity.
Procedures
CTX130 was manufactured from healthy donor T cells via CRISPR-Cas9 gene editing (appendix p 13). TRAC was disrupted and an anti-CD70 CAR expression cassette (delivered via recombinant adeno-associated virus vector) was inserted at the locus, disrupting TCR surface expression and minimising graft versus host disease risk. Expression of β2-microglobulin and CD70 were also disrupted to minimise MHC-mediated immune rejection of CTX130 and minimise fratricide, respectively.
Patients received lymphodepleting chemotherapy—ie, intravenous fludarabine 30 mg/m2 plus cyclo phosphamide 500 mg/m2 daily for 3 days—followed by intravenous CTX130 infusion on day 1. Dose escalation was performed using a standard 3 + 3 design. Three to six patients were enrolled at each dose level depending on the occurrence of dose-limiting toxicities. CTX130 was evaluated at dose levels 1–4 (in which dose level 1 was 3 × 107, dose level 2 was 1 × 108, dose level 3 was 3 × 108, and dose level 4 was 9 × 108 CAR+ T cells). There were three different treatment cohorts (ie, parts A1, A3, and A5). Part A1 treatment included fludarabine plus cyclophosphamide followed by day 1 infusion of CTX130 (appendix p 14). Part A3 treatment included fludarabine plus cyclophosphamide followed by day 1 infusion of CTX130 and day 5 CTX130 infusion without additional fludarabine plus cyclophosphamide. Part A5 treatment included fludarabine plus cyclophosphamide followed by day 1 CTX130 infusion and, for patients who had a complete response, partial response, stable disease, or progressive disease with clinical benefit per investigator assessment, fludarabine plus cyclophosphamide followed by day 35 CTX130 infusion.
Post-infusion assessments were scheduled for days 1, 2, 3, 5, 7, 10, 14, 21, 28, 35, 42, and 49, months 2–6, 9, 12, 15, 18, 21, and 24, and every 6 months thereafter up to 60 months. Local laboratory tests included a complete blood count with tests for differential serum chemistry, coagulation, viral serology, concentrations of IgA, IgG, and IgM, lymphocyte subsets, ferritin, C-reactive protein, and soluble IL-2 receptor (for potential cytokine release syndrome or haemophagocytic lymphohistiocytosis), cardiac markers, and pregnancy (appendix p 7). Demographic and sex data were collected using self-reporting or medical records. The options for reporting sex were male or female.
Adverse events were monitored from informed consent to 60 months, including the 7-day required hospitalisation per protocol and the dose-limiting toxicity monitoring period for the first 28 days after CTX130 infusion. Radiographic assessments occurred from screening to 60 months and included whole-body PET-CT or CT (or both) for response evaluation. Patients who discontinued from the regular assessment schedule attended annual secondary follow-up visits for safety data collection. Adverse events were graded per CTCAE version 5.0, except for cytokine release syndrome (per American Society for Transplantation and Cellular Therapy [ASTCT] criteria),13 neurotoxicity (per ASTCT criteria and CTCAE version 5.0), and graft versus host disease (Mount Sinai Acute GVHD International Consortium criteria).14 Treatment-emergent adverse events, defined as adverse events that start or worsen on or after the initial CTX130 infusion, were summarised by the Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. Serious adverse events were defined as events that resulted in death, initial or prolonged hospitalisation, disability, a congenital anomaly or birth defect, were life-threatening, or were otherwise considered an important or clinically significant medical event (appendix pp 8–9).
For patients with mycosis fungoides or Sézary syndrome who received CTX130 with two or more compartments involved at baseline, maximum percentage change from baseline by compartment (eg, skin, lymph nodes, and blood) was derived. For response assessment in the skin compartment, mSWAT score was used. For lymph nodes, sum of the product of perpendicular diameters of target lesions was calculated based on PET-CT results. For the blood compartment, the absolute count of aberrant cells was assessed by flow cytometry.
A safety review committee evaluated safety data after dose-limiting toxicity observation periods, which were the 28 days after each CTX130 infusion in which patients were monitored for the frequency and severity of adverse events and adverse events of special interest (appendix p 9) and the occurrence of dose-limiting toxicities. An independent data safety monitoring board reviewed safety data at biannual meetings and as needed.
Pharmacokinetic and pharmacodynamic analyses focused on the disposition of CTX130 over the first 28 days from a single infusion. For pharmacokinetic analyses, peak expansion of CTX130 was defined as the maximum CTX130 concentration after the initial nadir after each CTX130 infusion (day 1–28) and was assessed by droplet digital PCR. For pharmacodynamic analyses, peak expression was defined as the maximum serum cytokine concentration after CTX130 infusion to day 28 and was measured using qualified multiplex immunoassays (Luminex [Luminex Corporation, Austin, TX, USA] and Meso Scale Detection panels [Meso Scale Discovery, Gaithersburg, MD, USA]). RNAscope was used in patient C13 to evaluate CTX130 trafficking to tumour sites (appendix pp 10–12).
Outcomes
The primary objective was to evaluate the safety of escalating doses and dosing regimens of CTX130 in relapsing or refractory T-cell lymphomas. The primary endpoint was the incidence of adverse events (ie, dose-limiting toxicities within 28 days post-infusion).
Secondary endpoints were best overall response, objective response rate, duration of response, duration of response by best overall response, duration of clinical benefit, disease control rate, treatment failure-free survival, progression-free survival, overall survival, mycosis fungoides or Sézary syndrome disease response by compartment, time to response, incidence and severity of adverse events and clinically significant laboratory abnormalities, concentrations of CTX130 in blood over time, and patient-reported outcomes (see appendix pp 5–6 for definitions of all secondary endpoints). Secondary efficacy endpoints depending on tumour response were evaluated according to investigator assessment. Exploratory endpoints included concentration of CTX130 in tissues, cytokine concentration in blood, incidence of allogeneic haematopoietic stem-cell transplantation following CTX130 therapy, and biomarker analyses. Due to the small sample size at each dose level and the short duration of follow-up, only selected secondary and exploratory endpoints were analysed; duration of response by best overall response, duration of clinical benefit, treatment failure-free survival, time to response, patient-reported outcomes, disease control rate, progression-free survival, and overall survival were not analysed in this manuscript. Response in patients with peripheral T-cell lymphoma was assessed by Lugano response criteria.12 Response in patients with mycosis fungoides or Sézary syndrome was assessed in skin, lymph node, visceral, and blood compartments per Olsen 2011 criteria.15
Statistical analysis
There was no hypothesis testing. The sample size was calculated from the number of planned dose levels following a 3 + 3 design. For example, in study part A1, there were six planned dose levels, so the planned total sample size was 36.
Analyses of clinical activity were performed based on the full analysis set, comprising patients who received one or more CTX130 infusions and a day-28 response assessment, or discontinued the study before 28-day follow-up. The best overall response per investigator’s assessments post-CTX130 treatment was summarised for peripheral T-cell lymphoma and mycosis fungoides or Sézary syndrome separately by dose level, at dose level 3 and above, and overall. Patients with a non-evaluable tumour response or who discontinued before 28-day follow-up were considered non-responders. The proportion of patients who had a best overall response of complete response or partial response (objective response rate) and corresponding two-sided 95% CIs were provided. Duration of response was analysed using the Kaplan–Meier method for all patients who had a best overall response of complete response or partial response. Median duration of response with corresponding two-sided 95% CIs for peripheral T-cell lymphoma and mycosis fungoides or Sézary syndrome were provided separately. Duration of response was censored at the last adequate response assessment for patients who had not progressed or died if they did not receive stem-cell transplant. Duration of response was censored at the time of stem-cell transplantation for patients who had not progressed or died and received stem-cell transplant before the data cutoff. To evaluate the improvement in each involved compartment for patients with cutaneous T-cell lymphoma, the following post-hoc analysis was also performed. Percentage changes from baseline in mSWAT, the sum of the product of perpendicular diameters of target lesions based on CT scan results, and the malignant T cells measured in peripheral blood by flow cytometry were derived for the skin, lymph nodes, and blood compartment, respectively.
Safety data and baseline characteristics were summarised based on the safety analysis set, comprising patients who received one or more CTX130 infusions. Descriptive statistics were used to summarise safety data.
Pharmacokinetic and pharmacodynamic analyses were performed based on the safety analysis set. If there was no CTX130 expansion, all the timepoints would be CTX130 concentrations below the limit of detection and the patient’s peak expansion was imputed as 2.9 copies per μg, which is half the limit of detection. For pharmacodynamic analyses, peak expression (Cmax) was defined as the maximum serum cytokine concentration after CTX130 infusion to day 28. If the patient’s cytokine concentration was below the limit of detection, the Cmax of the cytokine was imputed as half the lower limit of quantification of each cytokine. CD70 expression was measured by immunohistochemistry (appendix p 10).
In all analyses, a patient was assigned to the dose level that corresponds to the first CTX130 infusion received. Statistical analyses and data visualisation were performed using SAS version 9.2 (or higher) or GraphPad Prism.
Role of the funding source
The funder of the study was involved in the study design, data collection, data analysis, data interpretation, and writing of the report.
Results
Between Aug 28, 2020, and May 30, 2023, 45 patients with T-cell lymphoma were assessed for eligibility, and 39 patients received CTX130 and were included in the safety and activity analyses (figure 1). The median age of patients was 63.0 years (IQR 47.0–68.0). 21 (54%) of 39 patients were female and 18 (46%) were male. 24 (62%) patients were White, eight (21%) were Black, three (8%) were Asian, three (8%) were from other racial or ethnic groups, and one (3%) was not reported. Of 39 patients who received CTX130, 22 (56%) had peripheral T-cell lymphoma (nine with adult T-cell leukaemia or lymphoma) and 17 (44%) had mycosis fungoides or Sézary syndrome. Patients with peripheral T-cell lymphoma had a median of 2.5 previous systemic therapy lines (IQR 1.3–4.0) and patients with mycosis fungoides or Sézary syndrome had a median of 5.0 previous systemic lines (5.0–7.0; table 1, appendix p 20). 23 patients received one CTX130 infusion and 16 received more than one (appendix p 14). 26 (67%) of 39 patients were treated at dose level 4. The median follow-up was 7.4 months (IQR 3.1–12.2).
Figure 1: Trial profile.
Six patients were treated in a different prespecified part of the study because they had a different disease (B-cell lymphoma) or they had received modified lymphodepletion. Therefore, they were excluded from the safety and activity analyses and are not shown in this figure.
Table 1:
Baseline characteristics
| Dose level 1 (n=4) |
Dose level 2 (n=4) |
Dose level 3 (n=5) |
Dose level 4 (n=26) |
All (n=39) |
|
|---|---|---|---|---|---|
| Median (IQR) age, years | 58.0 (48.0–64.0) | 66.0 (52.0–69.0) | 67.0 (65.0–72.0) | 60.5 (47.0–68.0) | 63.0 (47.0–68.0) |
| Sex | |||||
| Male | 3 (75%) | 2 (50%) | 2 (40%) | 11 (42%) | 18 (46%) |
| Female | 1 (25%) | 2 (50%) | 3 (60%) | 15 (58%) | 21 (54%) |
| Race | |||||
| White | 3 (75%) | 2 (50%) | 4 (80%) | 15 (58%) | 24 (62%) |
| Black or African American | 0 | 1 (25%) | 1 (20%) | 6 (23%) | 8 (21%) |
| Asian | 0 | 0 | 0 | 3 (12%) | 3 (8%) |
| Other | 0 | 0 | 0 | 1 (4%) | 1 (3%) |
| Multiple | 1 (25%) | 0 | 0 | 1 (4%) | 2 (5%) |
| Not reported | 0 | 1 (25%) | 0 | 0 | 1 (3%) |
| Type of lymphoma | |||||
| Peripheral T-cell lymphoma | 2 (50%) | 1 (25%) | 2 (40%) | 17 (65%) | 22 (56%) |
| Adult T-cell leukaemia or lymphoma | 1 (25%) | 1 (25%) | 1 (20%) | 6 (23%) | 9 (23%) |
| Peripheral T-cell lymphoma not otherwise specified | 1 (25%) | 0 | 0 | 7 (27%) | 8 (21%) |
| Angioimmunoblastic T-cell lymphoma | 0 | 0 | 1 (20%) | 3 (11.5) | 4 (10%) |
| Anaplastic large-cell lymphoma | 0 | 0 | 0 | 1 (4%) | 1 (3%) |
| Sézary syndrome or mycosis fungoides | 2 (50%) | 3 (75%) | 3 (60%) | 9 (35%) | 17 (44%) |
| Mycosis fungoides | 2 (50%) | 3 (75%) | 1 (20%) | 8 (31%) | 14 (36%) |
| Sézary syndrome | 0 | 0 | 2 (40%) | 1 (31%) | 3 (8%) |
| Large cell transformation | 1 (50%) | 3 (100%) | 2 (67%) | 5 (56%) | 11 (65%) |
| Clinical stage of Sézary syndrome or mycosis fungoides at enrolment | |||||
| IIB | 1 (50%) | 1 (33%) | 0 | 4 (44%) | 6 (35%) |
| IIIA | 0 | 0 | 0 | 1 (11%) | 1 (6%) |
| IIIB | 0 | 0 | 0 | 1 (11%) | 1 (6%) |
| IVA1 | 0 | 1 (33%) | 0 | 0 | 1 (6%) |
| IVA2 | 0 | 1 (33%) | 2 (66.7) | 2 (22%) | 5 (29%) |
| IVB | 1 (50%) | 0 | 1 (33%) | 0 | 2 (12%) |
| Missing | 0 | 0 | 0 | 1 (11%) | 1 (6%) |
| Clinical stage of other disease types at enrolment* | |||||
| III | 0 | 0 | 1 (50%) | 2 (12%) | 3 (14%) |
| IV | 2 (100%) | 1 (100%) | 1 (50%) | 13 (76.5) | 17 (77%) |
| Missing | 0 | 0 | 0 | 2 (12%) | 2 (9%) |
| Median (IQR) number of previous systemic therapy lines† | 3.0 (2.0–4.5) | 6.0 (5.0–7.0) | 5.0 (3.0–6.0) | 3.5 (2.0–5>0) | 4.0 (2.0–6.0)‡ |
Data are n (%), unless otherwise specified.
Other lymphomas are peripheral T-cell lymphoma not otherwise specified, anaplastic large-cell lymphoma, adult T-cell leukaemia or lymphoma, and angioimmunoblastic T-cell lymphoma.
Categories of previous lines of systemic therapy are included in the appendix (p 20).
For peripheral T-cell lymphoma, median number of previous lines was 2.5 (IQR 1.3–4.0); for mycosis fungoides or Sézary syndrome, median number of previous lines was 5.0 (IQR 5.0–7.0).
The most common grade 3–4 adverse events were neutropenia (14 [36%] of 39 patients), anaemia (11 [28%]), and thrombocytopenia (six [15%]; table 2). CTX130-related adverse events (appendix p 22) were reported in 37 (95%) of 39 patients, and grade 3 or worse CTX130-related adverse events were reported in 21 (54%) patients. Serious adverse events (appendix p 25) occurred in 25 (64%) patients, with CTX130-related serious adverse events occurring in 14 (36%) patients, the most common being cytokine release syndrome in 11 (28%) patients. Three patients had both cytokine release syndrome and another CTX130-related serious adverse event, which were grade 1 immune effector cell-associated neurotoxicity syndrome, grade 2 atrial fibrillation, and grade 3 haemophagocytic lymphohistiocytosis. The three patients who had CTX130-related serious adverse events but who did not have cytokine release syndrome had grade 2 immune effector cell-associated neurotoxicity syndrome (n=1), grade 3 pneumonia (n=1), and grade 3 febrile neutropenia, grade 2 influenza, and grade 4 neutropenia (n=1). 21 patients died, 16 from progressive disease and five from adverse events considered unrelated to CTX130 treatment. Adverse events resulting in death included pneumonia, sepsis, haemophagocytic lymphohistiocytosis, hypernatremia, and acute cardiac failure. There were no events of graft versus host disease.
Table 2:
Adverse events
| Grade 1–2 | Grade 3 | Grade 4 | Grade 5 | |
|---|---|---|---|---|
| Blood and lymphatic system disorders | ||||
| Neutropenia | 1 (3%) | 3 (8%) | 11 (28%) | 0 |
| Anaemia | 5 (13%) | 11 (28%) | 0 | 0 |
| Thrombocytopenia | 1 (3%) | 1 (3%) | 5 (13%) | 0 |
| Febrile neutropenia | 1 (3%) | 4 (10%) | 0 | 0 |
| Leukopenia | 0 | 1 (3%) | 0 | 0 |
| Pancytopenia | 0 | 0 | 1 (3%) | 0 |
| Investigations | ||||
| Neutrophil count decreased | 1 (3%) | 0 | 5 (13%) | 0 |
| Platelet count decreased | 0 | 1 (3%) | 3 (8%) | 0 |
| Alanine aminotransferase increased | 2 (5%) | 1 (3%) | 0 | 0 |
| Aspartate aminotransferase increased | 2 (5%) | 1 (3%) | 0 | 0 |
| White blood cell count decreased | 0 | 1 (3%) | 1 (3%) | 0 |
| CD4 lymphocytes decreased | 0 | 0 | 1 (3%) | 0 |
| Ejection fraction decreased | 0 | 1 (3%) | 0 | 0 |
| Electrocardiogram QT prolonged | 0 | 1 (3%) | 0 | 0 |
| Lymphocyte count decreased | 0 | 0 | 1 (3%) | 0 |
| Immune system disorders | ||||
| Cytokine release syndrome | 23 (59%) | 2 (5%) | 1 (3%) | 0 |
| Haemophagocytic lymphohistiocytosis | 0 | 2 (5%) | 0 | 1 (3%) |
| General disorders and administration site conditions | ||||
| Fatigue | 9 (23%) | 2 (5%) | 0 | 0 |
| Pyrexia | 9 (23%) | 0 | 0 | 0 |
| Pain | 4 (10%) | 1 (3%) | 0 | 0 |
| Nervous system disorders | ||||
| Headache | 13 (33%) | 0 | 0 | 0 |
| Burning sensation | 0 | 1 (3%) | 0 | 0 |
| Metabolic encephalopathy | 0 | 1 (3%) | 0 | 0 |
| Presyncope | 0 | 1 (3%) | 0 | 0 |
| Seizure | 0 | 1 (3%) | 0 | 0 |
| Syncope | 0 | 1 (3%) | 0 | 0 |
| Gastrointestinal disorders | ||||
| Nausea | 12 (31%) | 1 (3%) | 0 | 0 |
| Vomiting | 8 (21%) | 0 | 0 | 0 |
| Colitis | 0 | 1 (3%) | 0 | 0 |
| Infections and infestations | ||||
| Pneumonia | 1 (3%) | 2 (5%) | 0 | 1 (3%) |
| Cytomegalovirus infection | 1 (3%) | 0 | 1 (3%) | 0 |
| Sepsis | 0 | 1 (3%) | 0 | 1 (3%) |
| Urinary tract infection | 1 (3%) | 1 (3%) | 0 | 0 |
| Alpha haemolytic streptococcal infection | 0 | 1 (3%) | 0 | 0 |
| Cellulitis | 0 | 1 (3%) | 0 | 0 |
| Corynebacterium infection | 0 | 1 (3%) | 0 | 0 |
| Cytomegalovirus viraemia | 0 | 1 (3%) | 0 | 0 |
| Human herpesvirus 6 encephalitis | 0 | 1 (3%) | 0 | 0 |
| Infective tenosynovitis | 0 | 1 (3%) | 0 | 0 |
| Parainfluenzae virus infection | 0 | 1 (3%) | 0 | 0 |
| Pneumonia pseudomonal | 0 | 1 (3%) | 0 | 0 |
| Septic shock | 0 | 1 (3%) | 0 | 0 |
| Serratia sepsis | 0 | 1 (3%) | 0 | 0 |
| Sinusitis aspergillus | 0 | 1 (3%) | 0 | 0 |
| Staphylococcal sepsis | 0 | 1 (3%) | 0 | 0 |
| Stenotrophomonas infection | 0 | 0 | 1 (3%) 0 | |
| Wound infection | 0 | 1 (3%) | 0 | 0 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 8 (21%) | 0 | 0 | 0 |
| Hyperglycaemia | 1 (3%) | 2 (5%) | 0 | 0 |
| Hypercalcaemia | 1 (3%) | 0 | 1 (3%) 0 | |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 3 (8%) | 1 (3%) | 0 | 0 |
| Pathological fracture | 0 | 1 (3%) | 0 | 0 |
| Skin and subcutaneous tissue disorders | ||||
| Rash maculo-papular | 4 (10%) | 1 (3%) | 0 | 0 |
| Drug eruption | 0 | 1 (3%) | 0 | 0 |
| Vascular disorders | ||||
| Hypotension | 11 (28%) | 0 | 0 | 0 |
| Respiratory, thoracic, and mediastinal disorders | ||||
| Hypoxia | 0 | 1 (3%) | 0 | 0 |
| Pulmonary embolism | 0 | 1 (3%) | 0 | 0 |
| Cardiac disorders | ||||
| Cardiac failure | 0 | 1 (3%) | 0 | 0 |
| Cardiac failure acute | 0 | 0 | 0 | 1 (3%) |
| Neoplasms: benign, malignant, and unspecified | ||||
| Invasive ductal breast carcinoma | 0 | 1 (3%) | 0 | 0 |
| Post transplant lymphoproliferative disorder | 0 | 1 (3%) | 0 | 0 |
| Squamous cell carcinoma | 0 | 1 (3%) | 0 | 0 |
| Renal and urinary disorders | ||||
| Acute kidney injury | 0 | 1 (3%) | 0 | 0 |
| Endocrine disorders | ||||
| Adrenal insufficiency | 0 | 1 (3%) | 0 | 0 |
Data are n (%). Adverse events are included regardless of attribution. Grade 1–2 adverse events occurring in at least 20% of patients and all grade 3–5 adverse events are summarised.
Cytokine release syndrome (serious and non-serious) was reported in 26 (67%) of 39 patients (mostly grade ≤2; table 3). Grade 3 or worse cytokine release syndrome occurred at dose level 4. Median time to onset of cytokine release syndrome was 2.0 days (IQR 1.0–6.5) post-infusion and median duration was 2.0 days (1.0–3.0). 19 (73%) of 26 patients with cytokine release syndrome required management with tocilizumab, nine (35%) patients received steroids for additional management, and one (4%) patient received an additional anti-cytokine agent (anakinra).
Table 3:
Adverse events of special interest
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 | |
|---|---|---|---|---|---|
| Cytokine release syndrome | 10 (26%) | 13 (33%) | 2 (5%) | 1 (3%) | 0 |
| Immune effector cell-associated neurotoxicity syndrome | 2 (5%) | 2 (5%) | 0 | 0 | 0 |
| Haemophagocytic lymphohistiocytosis | 0 | 0 | 2 (5%) | 0 | 1 (3%) |
| Grade ≥3 infection | NA | NA | 7 (18%) | 1 (3%) | 2 (5%) |
| CTX130 infusion-related reaction | 1 (3%) | 1 (3%) | 0 | 0 | 0 |
| Cardiac failure | 0 | 0 | 1 (3%) | 0 | 1 (3%) |
Data are n (%). NA=not applicable.
Cytokine release syndrome occurred in 15 (65%) of 23 patients who received one CTX130 infusion. Increased incidence rate or severity of cytokine release syndrome was not observed with additional CTX130 infusions. Among 16 patients who received an additional post-response CTX130 infusion, 11 had grade 1–2 cytokine release syndrome, which occurred after initial and additional infusions (n=7), only after additional infusion (n=3), or only after initial infusion (n=1). In part A3 of the study, of six patients who received CTX130 infusions on day 1 and day 5, five patients developed grade 1–2 cytokine release syndrome after day 1, which resolved before day 5, with no cytokine release syndrome recurrences.
One patient treated at dose level 4 with peripheral T-cell lymphoma not otherwise specified and a history of lymphoma-associated haemophagocytic lymphohistiocytosis had grade 3 haemophagocytic lymphohistiocytosis concurrent with grade 4 cytokine release syndrome (dose-limiting toxicity). Onset of cytokine release syndrome occurred on day 12 post-infusion and resolved on day 17 post-treatment (with tocilizumab, steroids, and anakinra). Haemophagocytic lymphohistiocytosis and cytokine release syndrome were assessed as CTX130-related events. Two additional events of haemophagocytic lymphohistiocytosis were reported during the study, both considered related to disease progression, and one event resulted in death. No additional dose-limiting toxicities were observed.
At dose level 3 or higher, four (10%) of 39 patients developed grade 1–2 immune effector cell-associated neurotoxicity syndrome. Median time to onset was 3.0 days (IQR 1.8–5.5) post-infusion, and median duration was 2.0 days (IQR 1.0–2.0). All cases resolved after treatment with steroids or supportive management, or both.
Consistent with lymphodepleting chemotherapy, all patients developed grade 3–4 haematopoietic abnormalities. Of 25 patients who received one CTX130 infusion at dose level 3 or higher, CD3+ T-cell counts and white blood cell counts typically reached nadir within the first week post-chemotherapy and recovered by the second week (appendix p 15). Ten (26%) of 39 patients had grade 3 or worse infections, the most frequent of which was pneumonia (n=4). One patient with mycosis fungoides died approximately 8 weeks post-infusion due to pneumonia (considered unrelated to CTX130). One patient with adult T-cell leukaemia or lymphoma developed human herpesvirus 6 (HHV-6) encephalitis, which was unresponsive to antiviral therapy, and died approximately 11 weeks post-infusion from infectious complications of encephalitis (sepsis considered possibly related to lymphodepleting chemotherapy and unrelated to CTX130). Four additional patients had viral infection reactivations (grade 2 Epstein–Barr virus [EBV] and a single case each of grade 2, 3, and 4 cytomegalovirus). Among four patients with cutaneous T-cell lymphoma with grade 3 or worse infections, one had a skin-confined grade 3 wound infection that resolved within a week (considered unrelated to CTX130).
In one patient with peripheral T-cell lymphoma not otherwise specified, grade 5 acute cardiac failure occurred 22–24 days post-infusion in the setting of grade 4 cytokine release syndrome, grade 3 haemophagocytic lymphohistiocytosis, and grade 3 metabolic encephalopathy. Acute cardiac failure was considered possibly related to the patient’s history of coronary artery disease and non-ischaemic cardiomyopathy. In another patient with peripheral T-cell lymphoma not otherwise specified, grade 3 cardiac failure occurred 42 days post-infusion, which resolved after 11 days, and was considered possibly related to the primary condition and history of uncontrolled atrial fibrillation, pulmonary embolism, and doxorubicin exposure.
Four secondary malignancy events were observed, all in patients with cutaneous T-cell lymphoma. One patient with Sézary syndrome was diagnosed with EBV+ post-transplant lymphoproliferative disorder with CNS involvement at 5 months, was unresponsive to high-dose methotrexate, dexamethasone, and rituximab, and died (due to hypernatremia). A second patient with mycosis fungoides was diagnosed with invasive ductal breast carcinoma on day 44, in the setting of resolution of all skin lesions and lymphadenopathy, and persistence of a breast mass present at screening. The patient underwent a simple mastectomy on day 96 and the event was considered resolved. A third patient with Sézary syndrome was diagnosed with squamous cell carcinoma at day 30 based on skin punch biopsy of a pre-existing lesion that had been present before enrolment and was thought to be part of the patient’s T-cell lymphoma. The squamous cell carcinoma resolved with surgical excision on day 43. In the same patient, a different skin lesion that was new and not pre-existing was diagnosed as an EBV+ large B-cell lymphoma on day 40 and spontaneously resolved on day 73. All events were assessed by investigators as unrelated to CTX130. As for the EBV-associated malignancies, the investigators assessed them as related to immunosuppression associated with previous therapy or lymphodepleting chemotherapy, or both.
18 of 39 patients (46.2% [95% CI 30.1–62.8]) had an objective response. At dose level 3 or higher, 16 of 31 patients (51.6% [33.1–69.8]) had objective responses, including six (19.4% [7.5–37.5]) with a complete response and ten (32.3% [16.7–51.4]) with a partial response. Six of 12 patients (50.0% [21.1–78.9]) with mycosis fungoides or Sézary syndrome at dose level 3 or higher had a complete response (n=2) or partial response (n=4). Four of seven patients (57.1% [95% CI 18.4–90.1]) with large-cell trans formation had a response, including two with a complete response and two with a partial response, at dose level 3 or higher. Five patients with mycosis fungoides or Sézary syndrome were treated at dose level 1–2, with one patient having a partial response. At dose level 3 or higher, the median duration of response for patients with mycosis fungoides or Sézary syndrome was not reached (two of six patients progressed and four of six were censored) at time of data cutoff (May 30, 2023; figure 2A). At dose level 3 or higher, ten of 19 patients (52.6% [95% CI 28.9–75.6]) with peripheral T-cell lymphoma had a complete response (n=4) or partial response (n=6), including four with angioimmunoblastic T-cell lymphoma, four with adult T-cell leukaemia or lymphoma, and two with peripheral T-cell lymphoma not otherwise specified (figure 2B). At dose level 3 or higher, the median duration of response for patients with peripheral T-cell lymphoma was 2.5 months (95% CI 1.1 to non-evaluable); five of ten patients had disease progression and five of ten were censored. Three patients who responded to CTX130 underwent allogeneic stem-cell transplantation, with sustained remission after transplant, and without occurrence of secondary malignancy or CTX130-related serious adverse events or adverse events of special interest (range of follow-up post-transplantation was 12–14 months). Additional secondary endpoints, response by compartment, progression-free survival, overall survival, and disease control rate, are reported in the appendix (p 21).
Figure 2: CTX130 clinical activity across T-cell lymphomas.
Swimmer plot of patients with mycosis fungoides and Sézary syndrome (A) and patients with peripheral T-cell lymphoma (B). For patient identifiers, C indicates patients with cutaneous T-cell lymphoma and P indicates patients with peripheral T-cell lymphoma. *Patients initially treated at dose level 1 or 2. All other patients were treated at dose level 3 or 4. †In the setting of reinfusion, grey bars represent time from progressive disease to next response assessment.
In a post-hoc analysis, CTX130 activity was analysed across disease compartments. Of 17 patients with mycosis fungoides or Sézary syndrome, 16 had disease involvement in two or more compartments, and 13 of 16 patients showed improvement in two or more compartments (figure 3; appendix p 21). Responses were observed in all disease compartments in two patients. Of eight patients with mycosis fungoides or Sézary syndrome and global responses of stable disease, four patients had more than 50% (partial response level) reduction in lymph node compartments (n=2) or blood compartments (n=2), and two of four patients with global partial response had more than 90% disease reduction in one or more disease compartment (blood compartment n=1; lymph node and blood compartments n=1). Two patients with global complete response had near complete resolution of skin and nodal disease.
Figure 3: Waterfall plot of maximum percentage change from baseline by compartment.
Patients with cutaneous T-cell lymphoma (marked C for identification purposes) who received CTX130 with two or more compartments involved at baseline. Patients C1–12 and C14 had mycosis fungoides; patients C15–17 had Sézary syndrome. Note, patient C13 only had skin involvement and thus was not included in this waterfall plot. Analyses were performed post hoc. DL=dose level.
Pharmacokinetics analysis on whole blood samples of patients who received one CTX130 infusion at dose level 4 detected CTX130 at 20 min post-infusion, followed by redistribution approximately on day 2 to near the limit of detection in most patients, then rapid expansion, with maximum concentration observed around day 7. In most patients, CTX130 concentrations subsequently declined and were undetectable by day 28 (appendix p 16). Similar pharmacokinetics were observed at lower dose levels, and similar maximum concentration was observed when two infusions were administered (appendix p 17). Higher maximum concentrations of inflammatory cytokines were observed in patients who had cytokine release syndrome (appendix p 18). Analysis of CTX130 trafficking to tumour sites is shown in the appendix (p 16).
We explored the association between response and CD70 expression as a post-hoc analysis. Across T-cell lymphoma indications, baseline CD70 expression was at least 10% (by immunohistochemical analysis) in 20 patients, and 0–5% in two patients with adult T-cell leukaemia or lymphoma. Expression was not correlated with response (appendix pp 19–20). Analysis of on-treatment biopsies showed no statistically significant change in CD70 expression during the course of treatment, nor any loss of expression in patients who did not respond (appendix p 19).
Discussion
To our knowledge, this study is the first to evaluate CD70-targeted CAR T cells in T-cell lymphoma. This study investigated the safety and activity of CTX130 in a highly pretreated patient population with high-risk subtypes of mycosis fungoides or Sézary syndrome (eg, advanced stage ≥IIB, multicompartment disease, or large-cell transformation), peripheral T-cell lymphoma not otherwise specified, anaplastic large-cell lymphoma, adult T-cell leukaemia or lymphoma, and angioimmunoblastic T-cell lymphomas, and showed a manageable safety profile and encouraging responses at dose level 3 or higher, with 50.0% of patients (95% CI [21.1–78.9]) having a complete response or partial response in cutaneous T-cell lymphoma and 52.7% (28.9–75.6) having a complete or partial response in peripheral T-cell lymphoma.
Across the different subtypes of T-cell lymphoma, several responses were notably durable. At data cutoff, one patient with mycosis fungoides with skin and nodal involvement had a response for 20 months and one patient with adult T-cell leukaemia or lymphoma had a response for 9 months. Three patients who had responses to CTX130 underwent allogeneic stem cell transplantation, which is the only curative treatment for patients with relapsed or refractory disease. Other responses, especially in peripheral T-cell lymphoma not otherwise specified and angioimmunoblastic T-cell lymphoma, were short-lived (median duration of response was 2.5 months). This activity in a highly pretreated and heterogeneous population with T-cell lymphoma supports the continued investigation of CAR T-cell therapy in all T-cell lymphomas.
The safety profile of CTX130 was consistent with the CAR T-cell pharmacological class. The most common adverse event was cytokine release syndrome, occurring in 26 (67%) of 39 patients, with the majority being grade 1–2. Although there are no approved CD70-targeting CAR T cells, these rates are consistent with those of approved CD19-targeting CAR T-cell therapies (eg, tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel, and brexucabtagene autoleucel).
Because CD70 is transiently expressed in activated peripheral T lymphocytes and B lymphocytes and natural killer cells,16–18 grade 3 or worse infections were predefined adverse events of special interest. The rate of grade 3 or worse infections was 26%, which is similar to findings from CD19-targeting CAR T cell studies on lymphoma using similar lymphodepleting regimens (19–40%). Low rates of EBV infection occurred despite the association of germline CD70 loss with recurrent EBV-driven lymphoproliferative disorder and lymphoma.19 Only two cases of EBV infection in the same patient and two cases of EBV-associated secondary malignancies were observed, possibly reflecting the underlying increased risk of EBV disease due to profound immunosuppression in heavily pretreated patients with T-cell lymphoma, or the association with conditioning chemotherapy and cell therapy (or both). We observed one case of HHV-6 encephalitis, presenting as CNS-confined viral reactivation, which is a recognised complication of allogeneic stem-cell transplantation and has been observed with CD19-targeted CAR T cells.20,21 Of note, CTX130 was HHV-6 DNA-negative. The wide distribution of infectious causes was consistent with an underlying predisposition to infection in cutaneous T-cell lymphoma (due to skin barrier disruption and restricted T-cell repertoire22,23) and with previous T-cell targeting therapy, and, in the setting of blood cell count recoveries post-lymphodepleting chemotherapy, does not indicate a specific deficit in host cellular immunity with CD70-targeting CAR T cells.
This study suggests that allogeneic CAR T-cell manufacturing allows T cell-associated antigens such as CD70 to be safely assessed as targets for CAR T-cell therapies. Additionally, the allogeneic approach enables repeat infusions that can elicit responses, with similar rates of cytokine release syndrome.
Pharmacokinetics analysis of CTX130 from blood samples showed a pattern of detection, redistribution, rapid expansion (on day 7), and peripheral clearance for most patients by day 28. We noted shorter persistence of allogeneic CD70 CAR T cells than of autologous CD19-targeting CAR T cells in peripheral circulation; further study is needed to understand the clinical duration of response and the utility of blood-based or tissue-based detection. Nevertheless, a case study of a patient with mycosis fungoides showed that CTX130 trafficked to the tumour tissue site.
In our dataset, CD70 expression remained high across T-cell lymphomas, with a median expression level of more than 70% across indications. There was no evidence of correlation between expression level and clinical response. Furthermore, on-treatment biopsies showed that CD70 expression levels did not decrease over the course of treatment and were not correlated with response. Therefore, in this dataset, there was neither a threshold of CD70 expression for response nor an overall loss of antigen. However, tissue samples were not necessarily taken from the same lesion over time; therefore, conclusions could not be made about a particular lesion tracked through treatment. We also highlight that immunohistochemical analysis only captures CD70 expression as a snapshot in time at specific on-treatment collections, rather than for each lesion and tumour microenvironment.
Limitations of this study mainly resulted from the small sample size, making it difficult to compare the safety and activity of different planned dosing schedules, and limiting the ability to analyse the contribution of each individual infusion. Difficulties in adhering to planned repeat infusion schedules increased these challenges. Furthermore, this was a phase 1 study that enrolled patients with multiple T-cell lymphoma entities, and further investigation is warranted to elucidate different clinical and biological activity between each disease entity. Finally, assessment of duration of response was limited due to the proportion of censoring at the last response assessment before beginning alternative anticancer therapy, curtailing assessment of the duration of response of CTX130.
There remains opportunity to improve the depth and duration of response of CTX130, and a next-generation CAR T-cell therapy containing additional potency gene edits (CTX131) is in clinical development (CRSP-ONC-005, NCT05795595, CRSP-ONC-008, NCT06492304).
Supplementary Material
Research in context.
Evidence before this study
We searched PubMed with the search terms “peripheral T cell lymphoma”, “cutaneous T cell lymphoma”, “mycosis fungoides”, OR “Sézary syndrome” AND “CD70” OR “CD27” for articles published in English from Jan 1, 1990, to April 18, 2024. In terms of therapeutic approaches, a preclinical study showed high concentrations of CD70 in T-cell lymphomas and tumour shrinkage in xenograft mouse models with the antibody–drug conjugate SGN-CD70a. Results from a phase 1 study of 27 patients with CD70+ cutaneous T-cell lymphoma treated with an antibody that blocks CD70-CD27 signalling (ARGX-110; cusatuzumab) showed that six patients had an antitumour response and the antibody had a manageable safety profile.
Added value of this study
To our knowledge, this is the first reported trial of an allogeneic CAR T-cell therapy in mature T-cell lymphoma, especially adult T-cell leukaemia or lymphoma. We observed anti-tumour activity with this healthy donor-derived, gene-edited T-cell therapy across multiple mature T-cell lymphomas, both cutaneous and peripheral nodal subtypes, which express high concentrations of the target CD70. Global responses were observed across cutaneous T-cell lymphoma subtypes, with responses across skin, blood, and lymph node compartments. These results establish CD70 as a target for immune effector cell therapy.
Implications of all the available evidence
To our knowledge, CTX130 is the first CD70-directed CAR T-cell therapy showing activity in T-cell lymphoma. Data from this phase 1 study indicate a favourable benefit–risk profile for CTX130.
Acknowledgments
This study was funded by CRISPR Therapeutics. We thank the patients and their families. We also thank the staff members supporting the study at the clinical trial sites, the researchers involved in the preclinical development of the CAR T-cell construct, and the members of the data safety monitoring board. We also thank the CRISPR Therapeutics medical writing team members, Susan Gray, Tania Lee, and Jaya Vatsyayan, for providing manuscript preparation and editorial support. The medical writers were funded by CRISPR Therapeutics.
Funding
CRISPR Therapeutics.
Declaration of interests
SPI reports institutional support from CRISPR Therapeutics, Acrotech, and Rhizen, institutional contracts from CRISPR Therapeutics, Innate, Merck, Trillium/Pfizer, Seagen, DrenBio, and Acrotech, consulting fees from Yingli and Electra/Star, unpaid participation on an advisory board for Ranok Therapeutics, participation in the Indo American Cancer Association, and equity interest in IMPaRT.ai (Technology). RAS reports working as an investigator on a CRISPR Therapeutics trial, receipt of a Paul Calabresi Career Development Award K12 NIH grant, a grant to study CAR T in a disadvantaged population cohort (Kite), receipt of consulting fees and support for attending a consulting meeting from CRISPR Therapeutics, and receipt of consulting fees from BioHeng. PJH reports working as an investigator on a CRISPR Therapeutics trial, participation on an advisory board for Antengene, Gilead, iTeos Therapeutics, Janssen, and Pfizer, and receipt of medical writing support from Novartis. AP reports working as an investigator on a CRISPR Therapeutics trial and receipt of honoraria from Seattle Genetics, AstraZeneca, and AbbVie. JZ reports payment made from CRISPR Therapeutics for institutional research support and speaker bureau fees from Kyowa Kirin. FMF reports working as an investigator on a CRISPR Therapeutics trial, speaker fees from Seagen, honoraria from Kyowa Kirin and Acrotech, and serving as a volunteer officer on The United States Cutaneous Lymphoma Consortium. BH reports consulting fees from AbbVie, working as an investigator for Genentech, Celgene, CRISPR Therapeutics, Morphosys, Caribou Biosciences, Repare Therapeutics, Artiva Biotherapeutics, Newave, AstraZeneca, and ImmPACT Bio, payment for presentation by OncLive, MJH Life Sciences, Binaytara Foundation, Total Health Conferencing, Dava Oncology, and Curio Science, payment for preparation of educational materials from Eli Lilly, and participation on an advisory board for TG Therapeutics, ADC Therapeutics, Bristol Meyers Squibb, Novartis, GenMab, ImmPact Bio, SeaGen, Regeneron, and Caribou Biosciences. AB reports working as an investigator on a CRISPR Therapeutics trial, institutional research grants from Kite, Autolus, ATARA, TESSA, Angiocrine, Juno, Lyell, and CRISPR, and payment from Autolus and Kite for educational events. W-KW reports working as an investigator on a CRISPR Therapeutics trial. YHK reports working as an investigator on a CRISPR Therapeutics trial and institutional research support from CRISPR Therapeutics for this trial, institutional grants from Kyowa Kirin, Innate, Corvus, and Dren Bio, royalties from UpToDate, consulting fees from Citius, Kyowa Kirin, CRISPR Therapeutics, and Dren Bio, membership to the board of directors for the Cutaneous Lymphoma Foundation and International Society for Cutaneous Lymphomas, and being a panel member for NCCN. MSK reports working as an investigator on a CRISPR Therapeutics trial, receipt of research funding from Nutcracker Therapeutics, receipt of an NIH grant 1K08CA207882, and participation on an advisory board for Myeloid Therapeutics. AOH reports institutional support from CRISPR Therapeutics, Rhizen, Trillium, Kyowa Kirin, and Kymera. SMH reports institutional support from ADC Therapeutics, Affimed, Aileron, Celgene, CRISPR Therapeutics, Daiichi Sankyo, Forty Seven, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio, partial support for this trial from the NIH/NCI Cancer Center Support Grant P30CA008748, and receipt of payment for educational events from Abcuro, Autolus, Auxilus Pharma, Corvus, Cimeio Therapeutics, Daiichi Sankyo, Dren Bio, Kyowa Hakko Kirin, March Bio, ONO Pharmaceuticals, Secura Bio, Shoreline Biosciences, Takeda, Tubulis, and Yingli Pharma. JHM, LMW, AM, EH, AG, SDN, PS, ELC, SK, M-LD, JNP, ZL, QAH, and AK report CRISPR Therapeutics employment and equity interest. XSH reports working as a contractor for CRISPR Therapeutics. PS reports being an inventor on a patent application filed by CRISPR Therapeutics/Nkarta. SK and AK report support from CRISPR Therapeutics for travel or attending meetings.
Footnotes
See Online for appendix
Data sharing
De-identified data that underlie the results reported in the article, as well as information from the protocol, will be available following article publication. Researchers should submit a methodologically sound proposal for materials or data to medicalaffairs@crisprtx.com.
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Associated Data
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Supplementary Materials
Data Availability Statement
De-identified data that underlie the results reported in the article, as well as information from the protocol, will be available following article publication. Researchers should submit a methodologically sound proposal for materials or data to medicalaffairs@crisprtx.com.