Enteropathy-associated T-cell lymphoma (EATL) is a rare lymphoma arising in the setting of celiac disease. Multiagent anthracycline-based chemotherapy alone is associated with poor long-term outcomes with a median overall survival of only 7 months. In patients who achieve a response to firstline therapy and are eligible for autologous stem cell transplantation (SCT), 5-year median overall survival can be improved to 50% to 60%. Because ~50% of patients with EATL express the CD30 antigen, targeted therapy with brentuximab vedotin has been explored with promising outcomes. We have recently completed a phase 1/2 study showing safety and efficacy of chimeric antigen receptor (CAR)–modified T cells targeting the CD30 molecule (CD30 CAR T cells) in CD301 Hodgkin lymphoma. Here we describe a patient with multiply relapsed EATL after previous allogeneic SCT (allo-SCT) who achieved a durable remission with CD30 CAR T cells

Beaven, A.W.

Block, J.

Cheng, C.

Dotti, G.

Ghosh, N.

Grover, N.

Ivanova, A.

Morrison, K.

Savoldo, B.

Serody, J.

Voorhees, T.J.

Carolina Digital Repository

EXCEPTIONAL CASE REPORTLong-term remission in multiply relapsed enteropathy-associated T-celllymphoma following CD30 CAR T-cell therapyTimothy J. Voorhees,1 Nilanjan Ghosh,2 Natalie Grover,1 Jared Block,2 Catherine Cheng,1 Kaitlin Morrison,1 Anastasia Ivanova,1Gianpietro Dotti,1 Jonathan Serody,1 Barbara Savoldo,1 and Anne W. Beaven11University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; and 2Levine Cancer Institute, Atrium Health, Charlotte, NCKey Points•CD30 CAR T-cell ther-apy promoted a pro-longed remission ina patient with multiplyrelapsed EATL.IntroductionEnteropathy-associated T-cell lymphoma (EATL) is a rare lymphoma arising in the setting of celiacdisease.1 Multiagent anthracycline-based chemotherapy alone is associated with poor long-termoutcomes with a median overall survival of only 7 months.2,3 In patients who achieve a response to first-line therapy and are eligible for autologous stem cell transplantation (SCT), 5-year median overall survivalcan be improved to 50% to 60%.3-5 Because ;50% of patients with EATL express the CD30 antigen,targeted therapy with brentuximab vedotin has been explored with promising outcomes.6,7 We haverecently completed a phase 1/2 study showing safety and efficacy of chimeric antigen receptor (CAR)–modified T cells targeting the CD30 molecule (CD30 CAR T cells) in CD301 Hodgkin lymphoma.8 Herewe describe a patient with multiply relapsed EATL after previous allogeneic SCT (allo-SCT) whoachieved a durable remission with CD30 CAR T cells.Case descriptionA 69-year-old male with a history of celiac disease, which was well-controlled with a gluten-free diet for9 years, developed abdominal pain and nausea. He underwent endoscopy and biopsy, which revealedCD301 EATL of the small bowel. A positron emission tomography/computed tomography (PET/CT)scan at diagnosis demonstrated extensive hypermetabolic lymphadenopathy above and below thediaphragm and extranodal disease in the small bowel. The patient was refractory to cyclophosphamide,doxorubicin, vincristine, and prednisone (CHOP) and ifosfamide, carboplatin and etoposide (ICE), buthe achieved a partial response (PR) after 3 cycles of brentuximab vedotin and bendamustine andreceived consolidation therapy with a nonmyeloablative allo-SCT from a matched related donor. Hereceived maintenance brentuximab vedotin after allo-SCT, but treatment was discontinued after 5 cyclesbecause of neuropathy.Ten months after his allo-SCT, he developed a new cutaneous nodule, and a biopsy confirmed relapsedEATL. He achieved a complete response (CR) with local radiation and brentuximab vedotin but becamerefractory to brentuximab vedotin after 5 months. He subsequently was treated with 2 cycles ofromidepsin and donor lymphocyte infusion (DLI; 1.463 107 cells per kg) and achieved a short-lived PR(,3 months). He received 2 cycles of brentuximab vedotin and a second DLI (1.0 3 108 cells per kg)resulting in a brief CR lasting ,2 months. A new biopsy of a cervical lymph node confirmed relapsedCD301 EATL (Figure 1A-B). Given that his disease was refractory to chemotherapy and brentuximabvedotin, he was referred to the University of North Carolina (UNC) for treatment with CD30 CAR T cells.MethodsThis patient was treated on our phase 1b Institutional Review Board–approved clinical trial(NCT02690545). Lymphodepleting chemotherapy consisted of bendamustine 70 mg/m2 per day andfludarabine 30 mg/m2 per day followed by 23 108 CD30 CAR T cells per m2, manufactured at the UNCGood Manufacturing Practice–compliant facility (IND14688).8 Disease response was determined byPET/CT imaging at 6 weeks after CAR T-cell therapy using Lugano criteria.9 Cytokine release syndrome(CRS) was graded according to Lee’s criteria.10 Persistence of CD30 CAR T cells in vivo wasSubmitted 26 August 2020; accepted 26 October 2020; published online 1December 2020. DOI 10.1182/bloodadvances.2020003218.Presented in abstract form at the 12th Annual T-Cell Lymphoma Forum, La Jolla, CA,31 January 2020.© 2020 by The American Society of Hematology8 DECEMBER 2020 x VOLUME 4, NUMBER 23 5925determined by quantitative polymerase chain reaction that usedperipheral blood samples.8 Cytokines were measured in the plasmaby Luminex assay.Results and discussionThe CD30 CAR T-cell product characteristics were similar to thosedescribed for CAR T cells generated from patients with Hodgkinlymphoma.8 Specifically, after 20 days of ex vivo culture, the productwas composed of 99% T cells that expressed the CD30 CAR,which contained both CD81 (48%) and CD41 (50%) cells, withphenotypic characteristics of effector-memory T cells (CD45RA–CCR7–; 75%) and a modest population of central-memory T cells(CD45RA–CCR71; 10%). Of note, he maintained 100% donorT-cell chimerism before CAR T-cell production, making it likely thatCAR T cells were generated from the allograft. He received 3 daysof lymphodepleting chemotherapy followed by CD30 CAR T cellsat a dose of 2 3 108 CAR T cells per m2.8Treatment with lymphodepletion and infusion of CD30 CAR T cellswas well tolerated, with grade 3 or higher toxicities limited tolymphopenia during the first 6 weeks, which was most likely re-lated to lymphodepleting chemotherapy. The patient developedgrade 1 CRS on day 12, which corresponded to the peak ofCAR T-cell expansion and increased inflammatory cytokines, suchas interleukin-6 (IL-6) and interferon-g in the peripheral blood(Figure 1C). Other CRS-related parameters included elevatedlevels of C-reactive protein, ferritin, fibrinogen, and D-dimer. CRSresolved spontaneously by day 15 and did not require specifictherapy. Although expansion of CD30 CAR T cells in this patientwas associated with an increase in the homeostatic cytokinesIL-7 and IL-15 after lymphodepletion (Figure 1D), CD30 CART cells were no longer detectable by quantitative polymerasechain reaction 3 months after infusion.8Disease evaluation by PET/CT before receiving lymphodeple-tion and CD30 CAR T cells showed involvement of bilateralcervical, supraclavicular, and mediastinal nodes as well as a singlemesenteric node. All locations completely resolved 6 weeks afterCD30 CAR T-cell therapy (Figure 2). Routine imaging at 24 monthsrevealed continued remission, and the patient remains clinicallywell on follow-up physical examinations more than 30 monthsafter treatment.There is limited experience in manufacturing autologous CART cells from individuals with T-cell lymphomas (TCLs). Here weA BIL-6TNFaIFNgPCR706050403020100-7 0 7 14 21 28 35 42 49110100100010000100000Days post CAR-T cell infusionpg/mlCopies/ug DNAD-Dimer ng/mL DDU = 783Fibrinogen (mg/dL) = 561Ferritin (ng/mL) = 340CRP = 193.2Temp = 100.7C20151050-7 0 7 14 21 28 35 42 490.00.51.01.52.0Days post CAR-T cell infusionpg/mlALC (x1+03)Lymph (ALC)IL-2IL-15IL-7DFigure 1. Pre–CAR-T diagnostic biopsy, CD30 CAR-T expansion, and detection of homeostatic cytokines. Hematoxylin and eosin stain (A; scale bar, 100 mm) andCD30 antibody stain of the tumor biopsy before CAR T-cell therapy (B; scale bar, 200 mm). (C) Detection of CD30 CAR T-cell molecular signals by quantitative polymerasechain reaction (qPCR) and of the indicated cytokines over the course of the first 6 weeks after infusion. The star indicates evaluation of the listed parameters during the CRSevent. (D) Detection of IL-2, IL-7, and IL-15 in the plasma and lymphocyte counts over the course of the first 6 weeks after infusion. ALC, absolute lymphocyte count; CRP,C-reactive protein; DDU, D-dimer unit; IFNg, interferon-g; TNFa, tumor necrosis factor-a.5926 VOORHEES et al 8 DECEMBER 2020 x VOLUME 4, NUMBER 23show the feasibility of achieving therapeutic doses of CD30 CART cells in a patient with EATL. To our knowledge, this is the first caseof EATL treated with CAR T-cell therapy. In this patient, who had notachieved a durable response with 6 previous lines of therapy,including brentuximab vedotin, allo-SCT, and multiple DLIs, we areencouraged by both the depth and duration of response after CD30CAR T-cell therapy. Given his previous history of allo-SCT and100% donor chimerism at the time of CAR T-cell production, wesuspect that the CD30 CAR T cells were produced from theallograft. The impact of previous allo-SCT on the success of CD30CAR T-cell treatment in this patient is not known, although thisshould be investigated in future studies.There is very limited experience with CD30 CAR T-cell therapy intreating patients with CD301 TCLs. The patient described in thisreport was the only patient with EATL treated with CD30 CART cells on our clinical trial. An additional adult with CD301 Sézarysyndrome was treated with the same lymphodepletion and celldose, achieved a PR at 6 weeks with reduction in his modifiedSeverity Weighted Assessment Tool (mSWAT) score from 26 to 1,but developed a clinical relapse after 9 weeks of follow-up. Ramoset al8 reported phase 1 dose escalation results of CD30 CART cells without lymphodepletion chemotherapy, which included 2patients with anaplastic large cell lymphoma (ALCL). The firstpatient, who had cutaneous anaplastic lymphoma kinase–negativeALCL, received a dose of 2 3 107 CAR T cells per m2 (one-loglower than our patient) with no response. The second patient withsystemic anaplastic lymphoma kinase–positive ALCL achieveda durable CR (9 months) after receiving 4 separate CD30 CART-cell infusions at a dose of 2 3 108 CAR T cells per m2.11 Asecond group, evaluating a slightly different CD30 CAR construct,reported 1 patient with cutaneous ALCL treated with CD30 CART cells at a dose of 1.5 3 107 cells per kg without previouslymphodepletion who obtained a PR for 3 months.12Although only ALCL and certain subsets of TCLs express CD30,targeting this molecule with a CAR still offers numerous advan-tages. First, fratricide is minimal, which guarantees that there will beno deleterious effects during T-cell product manufacturing. This is incontrast to CAR T cells targeting other T-cell lineage–associatedantigens, such as CD7, CD5, and CD4.13-15 Second, CD30 CART cells have a very tolerable safety profile compared with toxicitiesanticipated with CAR T cells targeting other T-cell lineage antigens.CD30 CAR T cells have no reported deleterious effects on cellularimmunity, suggesting that the risk for opportunistic infectionsshould be minimal. In addition, episodes of CRS seem less severecompared with those in which CAR T cells target other antigenssuch as CD19. Finally, neurotoxicity has not been observed inpatients receiving CD30 CAR T-cell therapy.Well-designed clinical trials are needed to expand our understand-ing of and overcome obstacles when using CD30 CAR T cells inTCL. The remarkable response observed in this patient should beconfirmed in a larger phase 2 trial. On the basis of experience withCD19 CAR expansion and persistence, CAR T cells can be used assurrogate markers for clinical outcomes. It will be important todevelop methods for increasing expansion and persistence of theinfused CD30 CAR T cells and therefore improve clinical outcomes.In addition, each distinct TCL subset may present differentobstacles to the persistence of CAR T cells, possibly related tothe tumor environment. Finally, any effect of CD30 antigen densityon clinical responses should be investigated. To this end, UNC iscurrently enrolling patients with relapsed/refractory CD301 periph-eral TCL in a phase 2 trial that uses 2 sequential CD30 CAR T-cellinfusions at the recommended phase 2 dose of 2 3 108 CART cells per m2 (NCT04083495).AcknowledgmentsThis work was supported by a grant from the National Heart, Lung,and Blood Institute, National Institutes of Health (RO1HL114564)(B.S.), by the University Cancer Research Fund at the LinebergerComprehensive Cancer Center (B.S. and G.D.), and by a grant fromStand Up To Cancer (7000000853) (G.D.).AuthorshipContribution: T.J.V., N. Grover, B.S., and A.W.B. conducted the re-search and wrote the manuscript; A.W.B., N. Ghosh, J.B., and C.C.participated in the patient’s care; T.J.V., G.D., B.S., N. Grover, andJ.S. discussed and interpreted the results; and K.M., A.I., and J.S.wrote the clinical protocol.Conflict-of-interest disclosure: Competing interests of authorsfrom the University of North Carolina are managed in accordance withinstitutional policies. B.S., G.D., and J.S. have a pending patent con-cerning the CD30 CAR-T product presented in this article. J.S. hasfiled an intellectual property patent regarding the use of STINGagonists to enhance CAR T-cell therapy. N. Grover served as a con-sultant for Tessa Therapeutics, has received research funding fromGenentech, and has served on an advisory board for Kite Pharma.T.J.V. received research funding from AstraZeneca. The University ofNorth Carolina has a research collaboration with Tessa Therapeutics.The remaining authors declare no competing financial interests.ORCID profiles: T.J.V., 0000-0001-7603-6454; N. Grover,0000-0002-1346-3157; J.S., 0000-0003-4568-1092.Correspondence: Timothy J. Voorhees, Lineberger Compre-hensive Cancer Center, University of North Carolina–Chapel Hill,170 Manning Dr, CB 7305, Chapel Hill, NC 27599-7305; e-mail:timothy.voorhees@unchealth.unc.edu.Before Infusion 6 Weeks After InfusionFigure 2. Durable CR after CD30 CAR T-cell therapy.Patient with multiply relapsed EATL. Before lymphodepletionand CD30 CAR T-cell infusion, disease involved the bilateralcervical, supraclavicular, mediastinal, hilar, and a single mesen-teric lymph node. Six weeks after infusion, the patient achieveda Deauville score of 1 and CR. Additional disease assessmentsat 6, 12, and 24 months have continued to show CR.8 DECEMBER 2020 x VOLUME 4, NUMBER 23 CD30 CAR T CELLS RESULT IN REMISSION FOR EATL 5927References1. Di Sabatino A, Biagi F, Gobbi PG, Corazza GR. How I treat enteropathy-associated T-cell lymphoma. Blood. 2012;119(11):2458-2468.2. Wöhrer S, Chott A, Drach J, et al. Chemotherapy with cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone (CHOEP) is not effective inpatients with enteropathy-type intestinal T-cell lymphoma. Ann Oncol. 2004;15(11):1680-1683.3. Sieniawski M, Angamuthu N, Boyd K, et al. Evaluation of enteropathy-associated T-cell lymphoma comparing standard therapies with a novel regimenincluding autologous stem cell transplantation. Blood. 2010;115(18):3664-3670.4. Jantunen E, Boumendil A, Finel H, et al; Lymphoma Working Party of the EBMT. Autologous stem cell transplantation for enteropathy-associated T-celllymphoma: a retrospective study by the EBMT. 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Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Oncotarget. 2017;8(68):112783-112796.5928 VOORHEES et al 8 DECEMBER 2020 x VOLUME 4, NUMBER 23

Long-term remission in multiply relapsed enteropathy-associated T-cell lymphoma following CD30 CAR T-cell therapy

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Long-term remission in multiply relapsed enteropathy-associated T-cell lymphoma following CD30 CAR T-cell therapy

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