PD-L1 expression predicts efficacy in the phase II SPiReL trial with MVP-S, pembrolizumab, and low-dose CPA in R/R DLBCL.
PD-L1
check-point inhibitor
diffuse large B cell lymphoma
immunotherapy
maveropepimut-S
Journal
European journal of haematology
ISSN: 1600-0609
Titre abrégé: Eur J Haematol
Pays: England
ID NLM: 8703985
Informations de publication
Date de publication:
Aug 2023
Aug 2023
Historique:
revised:
11
04
2023
received:
28
11
2022
accepted:
12
04
2023
medline:
19
7
2023
pubmed:
9
5
2023
entrez:
9
5
2023
Statut:
ppublish
Résumé
Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) have limited treatment options. R/R DLBCL patients, who were mostly ineligible for ASCT due to age or comorbidities, were treated with maveropepimut-S (MVP-S, previously DPX-Survivac) a survivin directed T cell educating therapy, pembrolizumab, and intermittent low-dose cyclophosphamide. We identified, using univariate analysis, a subset of patients with enhanced ORR, PFS and DOR. Patients with baseline CD20+/PD-L1 expression had an ORR of 46% (6/13) and the disease control rate was 10/13 (77%). The PFS and OS of the positive CD20+/PD-L1 patients were 7.1 months and 17.4 months, whereas in the intent-to-treat (ITT) population of 25 enrolled patients, the ORR was 28% (7/25), median PFS and OS were 4.2 months and 10.1 months respectively. A total of 6/7 clinical responders occurred in CD20+/PD-L1 patients. The regimen was well-tolerated, requiring only minor dose modifications and one discontinuation. Grade 1 or 2 injection site reactions occurred in 14/25, (56%). Statistically significant associations were also seen between PFS and; injection site reactions; and ELISpot response to survivin peptides, both identifying the mechanistic importance of specific immune responses to survivin. This immunotherapy combination was found to be active and safe in this clinically challenging patient population.
Sections du résumé
BACKGROUND
BACKGROUND
Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) have limited treatment options.
METHODS
METHODS
R/R DLBCL patients, who were mostly ineligible for ASCT due to age or comorbidities, were treated with maveropepimut-S (MVP-S, previously DPX-Survivac) a survivin directed T cell educating therapy, pembrolizumab, and intermittent low-dose cyclophosphamide.
FINDINGS
RESULTS
We identified, using univariate analysis, a subset of patients with enhanced ORR, PFS and DOR. Patients with baseline CD20+/PD-L1 expression had an ORR of 46% (6/13) and the disease control rate was 10/13 (77%). The PFS and OS of the positive CD20+/PD-L1 patients were 7.1 months and 17.4 months, whereas in the intent-to-treat (ITT) population of 25 enrolled patients, the ORR was 28% (7/25), median PFS and OS were 4.2 months and 10.1 months respectively. A total of 6/7 clinical responders occurred in CD20+/PD-L1 patients. The regimen was well-tolerated, requiring only minor dose modifications and one discontinuation. Grade 1 or 2 injection site reactions occurred in 14/25, (56%). Statistically significant associations were also seen between PFS and; injection site reactions; and ELISpot response to survivin peptides, both identifying the mechanistic importance of specific immune responses to survivin.
INTERPRETATION
CONCLUSIONS
This immunotherapy combination was found to be active and safe in this clinically challenging patient population.
Substances chimiques
pembrolizumab
DPT0O3T46P
Survivin
0
B7-H1 Antigen
0
Types de publication
Clinical Trial, Phase II
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
191-200Subventions
Organisme : IMV Inc.
Organisme : Merck
Informations de copyright
© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.
Références
Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808.
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184-4190.
Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56.
Crump M. Management of relapsed diffuse large B-cell lymphoma. Hematol Oncol Clin North Am. 2016;30(6):1195-1213.
Salles G, Duell J, Gonzalez Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988.
Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165.
Czuczman MS, Trněný M, Davies A, et al. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of Lenalidomide versus Investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017;23(15):4127-4137.
Hou K, Yu Z, Jia Y, et al. Efficacy and safety of ibrutinib in diffuse large B-cell lymphoma: a single-arm meta-analysis. Crit Rev Oncol Hematol. 2020;152:103010.
Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol. 2018;15(1):31-46.
Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: a phase I trial. J Clin Oncol. 2021;39(18):1959-1970.
van der Horst HJ, de Jonge AV, Hiemstra IH, et al. Epcoritamab induces potent anti-tumor activity against malignant B-cells from patients with DLBCL, FL and MCL, irrespective of prior CD20 monoclonal antibody treatment. Blood Cancer J. 2021;11(2):38.
Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014-1022.
Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape. Curr Opin Immunol. 2014;27:16-25.
Lladser A, Sanhueza C, Kiessling R, Quest AF. Is survivin the potential Achilles' heel of cancer? Adv Cancer Res. 2011;111:1-37.
Berinstein NL, Karkada M, Oza AM, et al. Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients. Onco Targets Ther. 2015;4(8):e1026529.
Zhang Y, Wang J, Sui X, et al. Prognostic and clinicopathological value of Survivin in diffuse large B-cell lymphoma: a meta-analysis. Medicine. 2015;94(36):e1432.
Weir GM, Hrytsenko O, Quinton T, Berinstein NL, Stanford MM, Mansour M. Anti-PD-1 increases the clonality and activity of tumor infiltrating antigen specific T cells induced by a potent immune therapy consisting of vaccine and metronomic cyclophosphamide. J Immunother Cancer. 2016;4:68.
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586.
Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19(13):3462-3473.
Ansell SM, Minnema MC, Johnson P, et al. Nivolumab for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for or having failed autologous transplantation: a single-arm phase II study. J Clin Oncol. 2019;37(6):481-489.
Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol. 2016;34(23):2698-2704.
Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano classification lymphoma response criteria in the era of immunomodulatory therapy. Blood. 2016;128(21):2489-2496.
Kline J, Godfrey J, Ansell SM. The immune landscape and response to immune checkpoint blockade therapy in lymphoma. Blood. 2020;135(8):523-533.
Kiyasu J, Miyoshi H, Hirata A, et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood. 2015;126(19):2193-2201.
Kwon D, Kim S, Kim PJ, et al. Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas. Histopathology. 2016;68(7):1079-1089.
Ahearne MJ, Bhuller K, Hew R, Ibrahim H, Naresh K, Wagner SD. Expression of PD-1 (CD279) and FoxP3 in diffuse large B-cell lymphoma. Virchows Arch. 2014;465(3):351-358.
Godfrey J, Tumuluru S, Bao R, et al. PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell-inflamed phenotype. Blood. 2019;133(21):2279-2290.
Georgiou K, Chen L, Berglund M, et al. Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas. Blood. 2016;127(24):3026-3034.
Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e522.
Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800.
Hamadani M, Radford J, Carlo-Stella C, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021;137(19):2634-2645.
Goy A, Ramchandren R, Ghosh N, et al. Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non-germinal center B-cell-like DLBCL. Blood. 2019;134(13):1024-1036.