Trial Watch

Figures & data

Table 1. Recently published clinical trials investigating the safety and efficacy of ACT-based immunotherapy in cancer patients

Indication(s)	Approach	N° of patients	Safety	Efficacy	Ref.
AML	Autologous T cells expressing a Lewis Y antigen-targeting CAR	4	No Grade 3–4 side effects	3 patients achieved objective responses	107
B-cell ALL	Autologous T cells expressing a CD19-targeting CAR	5	Raise in circulating cytokines in some patients, requiring lymphotoxic steroid therapy	All patients achieved minimal residual disease-negative complete remission upon treatment	58
		2	High number of Grade 3–4 side effects and cytokine-release syndrome	All patients achieved complete remission, 1 relapsed 2 mo after treatment owing to the surge of a CD19^- leukemic clone	106
B-cell neoplasms	Allogeneic T cells expressing a CD19-targeting CAR	10	No severe toxicities, the most common side effects being transient hypotension and fever	3 patients achieved objective responses	108
	Allogeneic VSCs expressing a CD19-targeting CAR	8	No infusion-related toxicities	2 patients with relapsing disease achieved objective responses, 2 patients in remission remained so for > 8 we and > 9 mo post-treatment	109
Breast carcinoma	Autologous T cells activated with MCF-7 lysate-pulsed DCs	16	n.a.	7 patients exhibited an immunological response to therapy, correlating with prolonged overall survival	113
HCC	Autologous PBLs plus DCs pulsed with autologous tumor lysates	42	No severe toxicity, the most common side effects being Grade 1 skin reactions	Adjuvant immunotherapy yielded 5-y overall and disease-free survival rates of 64.3% and 35.7%, respectively	115
Lymphoma	Autologous EBV- specific T cells	50	No infusion-related toxicities	28 patients experienced remission and 21 achieved objective responses	110
Melanoma	CD8^+ T cell-enriched or young TILs	69	Grade 3 febrile neutropenia and Grade 4 sepsis in several patients	12/34 patients treated with young TILs and 7/35 patients receiving CD8+ T cell-enriched TILs responded to therapy	111
	Young TILs plus high-dose IL-2	80	Pulmonary congestion and hypotension in > 20% of patients	18 patients achieved a partial remission and 5 a complete remission	112
Nasopharyngeal carcinoma	EBV-specific CTLs plus gemcitabine and carboplatin	35	No severe toxicity, the most common side effects being Grade 1–2 fatigue and myalgia	Overall response rate of 71.4%, median OS and DFS of 29.9 and 7.6 mo, respectively	114
RCC	CIK cells plus high-dose IL-2	29	n.a.	Partial responses were documented in 4 individuals, disease stabilization in 18 subjects, and progressive disease in 7 patients; 1-y OS rate of 82.8%	116
	Autologous T cells expressing a CA9-targeting CAR	12	Grade 2–4 elevations of hepatic enzymes in 8 patients	No clinical responses were recorded	117
Esophageal carcinoma Melanoma Synovial sarcoma	Autologous T cells expressing a MAGE-A3-targeting TCR	9	Fatal leukoencephalopathy in 2 patients, Parkinson-like symptoms in 1 patient	5 patients experienced disease regression	101

Abbreviations. ACT, adoptive cell transfer; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CA9, carbonic anhydrase IX; CAR, chimeric antigen receptor; CIK, cytokine-induced cell; CTL, cytotoxic T lymphocyte; DC, dendritic cell; DFS, disease-free survival; EBV, Epstein-Barr virus; HCC, hepatocellular carcinoma; IL-2, interleukin-2; MAGE-A3, melanoma antigen family A3; OS, overall survival; PBL, peripheral blood lymphocyte; RCC, renal cell carcinoma; TCR, T-cell receptor; TIL, tumor-infiltrating lymphocyte; VSC, virus-specific T cells. *Between 2013, March 1st and the date of submission.

Table 2. Clinical trials recently launched to evaluate the safety and efficacy of ACT-based immunotherapy in cancer patients.*

Indication(s)	Approach	Phase	Status	Notes	Ref.
Acute myeloid leukemia	Autologous T cells expressing a CD33-specific CAR	I/II	Recruiting	As a standalone intervention	NCT01864902
ALL	Autologous T cells expressing a CD19-specific CAR	I	Recruiting	Combined with cyclophosphamide	NCT01860937
		II	Recruiting	As a standalone intervention	NCT02030847
ALL CLL NHL	Autologous T cells expressing a CD19-specific CAR	I/II	Recruiting	As a standalone intervention	NCT01865617
		I	Not yet recruiting	As a standalone intervention	NCT02050347
Cholangiocarcinoma	Autologous CIK cells	I/II	Recruiting	As a standalone intervention	NCT01868490
CLL NHL	Autologous T cells expressing a CD19-specific CAR	I	Not yet recruiting	As a standalone intervention	NCT01853631
Colorectal carcinoma	Autologous CIK cells	II	Recruiting	After adjuvant or neoadjuvant therapy	NCT01839539
Hepatocellular carcinoma	Activated T lymphocytes	II	Active, not recruiting	As a standalone intervention	NCT01897610
Leukemia Lymphoma	Autologous T cells expressing a CD19-specific CAR	I/II	Recruiting	As a standalone intervention	NCT02028455
		n.a.	Recruiting	As a standalone intervention	NCT01864889
Melanoma	Autologous TGFβ1 DNR-expressing PBLs	I	Not yet recruiting	As a standalone intervention	NCT01955460
	Autologous CD8^+ PBLs	II	Not yet recruiting	Combined with ipilimumab	NCT02027935
	Conventional TILs	I	Not yet recruiting	As a standalone intervention	NCT01883297
			Recruiting	Combined with a DC-based vaccine	NCT01946373
		II	Not yet recruiting	As a standalone intervention	NCT01995344
					NCT01883323
			Recruiting	As a standalone intervention	NCT01807182
					NCT01814046
	Young TILs	II	Recruiting	As a standalone intervention	NCT01993719
Multiple myeloma	Activated MILs	II	Recruiting	Combined with a lenalidomide-based regimen	NCT01858558
	Autologous T cells expressing a CD138-specific CAR	I/II	Recruiting	As a standalone intervention	NCT01886976
	Autologous T cells expressing a NY-ESO-1-specific TCR	I/II	Recruiting	As a standalone intervention	NCT01892293
Neuroblastoma	Autologous T cells expressing a GD2-specific TCR	I	Recruiting	Inducible caspase-9- based suicide system	NCT01822652
NHL	Autologous T cells expressing a CD19-specific CAR	I	Recruiting	As a standalone intervention upon autologous HSCT	NCT01815749
					NCT01840566
			Not yet recruiting	As a standalone intervention upon autologous HSCT	NCT02051257
Solid tumors	Autologous T cells expressing a EGFR-specific CAR	I/II	Recruiting	As a standalone intervention	NCT01869166
	Autologous T cells expressing a HER2-specific CAR	I/II	Recruiting	As a standalone intervention	NCT01935843
	Autologous T cells expressing a NY-ESO-1-specific TCR	II	Recruiting	As a standalone intervention	NCT01967823

Abbreviations. ACT, adoptive cell transfer; ALL, acute lymphocytic leukemia; CAR, chimeric antigen receptor; CIK, cytokine-induced killer; CLL, chronic lymphocytic leukemia; DC, dendritic cell; DNR, dominant negative receptor; EGFR, epidermal growth factor receptor; HSCT, hematopoietic stem cell transplantation; MIL, marrow-infiltrating lymphocyte; NHL, non-Hodgkin lymphoma; PBL, peripheral blood lymphocyte; TCR, T-cell receptor; TGFβ1, transforming growth factor β1; TIL, tumor-infiltrating lymphocyte. *Between 2013, March 1st and the date of submission.

Ritchie DS, Neeson PJ, Khot A, Peinert S, Tai T, Tainton K, Chen K, Shin M, Wall DM, Hönemann D, et al. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther 2013; 21:2122 - 9; http://dx.doi.org/10.1038/mt.2013.154; PMID: 23831595

 PubMed Web of Science ®Google Scholar

Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5:177ra38; http://dx.doi.org/10.1126/scitranslmed.3005930; PMID: 23515080

 PubMed Web of Science ®Google Scholar

Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368:1509 - 18; http://dx.doi.org/10.1056/NEJMoa1215134; PMID: 23527958

 PubMed Web of Science ®Google Scholar

Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, Hakim FT, Halverson DC, Fowler DH, Hardy NM, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 2013; 122:4129 - 39; http://dx.doi.org/10.1182/blood-2013-08-519413; PMID: 24055823

 PubMed Web of Science ®Google Scholar

Cruz CR, Micklethwaite KP, Savoldo B, Ramos CA, Lam S, Ku S, Diouf O, Liu E, Barrett AJ, Ito S, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 2013; 122:2965 - 73; http://dx.doi.org/10.1182/blood-2013-06-506741; PMID: 24030379

 PubMed Web of Science ®Google Scholar

Domschke C, Ge Y, Bernhardt I, Schott S, Keim S, Juenger S, Bucur M, Mayer L, Blumenstein M, Rom J, et al. Long-term survival after adoptive bone marrow T cell therapy of advanced metastasized breast cancer: follow-up analysis of a clinical pilot trial. Cancer Immunol Immunother 2013; 62:1053 - 60; http://dx.doi.org/10.1007/s00262-013-1414-x; PMID: 23595207

 PubMed Web of Science ®Google Scholar

Shimizu K, Kotera Y, Aruga A, Takeshita N, Katagiri S, Ariizumi SI, Takahashi Y, Yoshitoshi K, Takasaki K, Yamamoto M. Postoperative dendritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive hepatocellular carcinoma. Hum Vaccin Immunother 2014; 10; Forthcoming http://dx.doi.org/10.4161/hv.27678; PMID: 24419174

 PubMed Web of Science ®Google Scholar

Bollard CM, Gottschalk S, Torrano V, Diouf O, Ku S, Hazrat Y, Carrum G, Ramos C, Fayad L, Shpall EJ, et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol 2013; Forthcoming http://dx.doi.org/10.1200/JCO.2013.51.5304; PMID: 24344220

 PubMed Web of Science ®Google Scholar

Dudley ME, Gross CA, Somerville RP, Hong Y, Schaub NP, Rosati SF, White DE, Nathan D, Restifo NP, Steinberg SM, et al. Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol 2013; 31:2152 - 9; http://dx.doi.org/10.1200/JCO.2012.46.6441; PMID: 23650429

 PubMed Web of Science ®Google Scholar

Besser MJ, Shapira-Frommer R, Itzhaki O, Treves AJ, Zippel DB, Levy D, Kubi A, Shoshani N, Zikich D, Ohayon Y, et al. Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res 2013; 19:4792 - 800; http://dx.doi.org/10.1158/1078-0432.CCR-13-0380; PMID: 23690483

 PubMed Web of Science ®Google Scholar

Chia WK, Teo M, Wang WW, Lee B, Ang SF, Tai WM, Chee CL, Ng J, Kan R, Lim WT, et al. Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther 2014; 22:132 - 9; http://dx.doi.org/10.1038/mt.2013.242; PMID: 24297049

 PubMed Web of Science ®Google Scholar

Wang Z, Zhang Y, Liu Y, Wang L, Zhao L, Yang T, He C, Song Y, Gao Q. Association of myeloid-derived suppressor cells and efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma patients. J Immunother 2014; 37:43 - 50; http://dx.doi.org/10.1097/CJI.0000000000000005; PMID: 24316555

 PubMed Web of Science ®Google Scholar

Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R, et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther 2013; 21:904 - 12; http://dx.doi.org/10.1038/mt.2013.17; PMID: 23423337

 PubMed Web of Science ®Google Scholar

Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, Dudley ME, Feldman SA, Yang JC, Sherry RM, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013; 36:133 - 51; http://dx.doi.org/10.1097/CJI.0b013e3182829903; PMID: 23377668

 PubMed Web of Science ®Google Scholar