T-Cell Therapy for Lymphoma Using Nonengineered Multiantigen-Targeted T Cells Is Safe and Produces Durable Clinical Effects

Abstract

Purpose: Patients with relapsed lymphomas often fail salvage therapies including high-dose chemotherapy and mono-antigen-specific T-cell therapies, highlighting the need for nontoxic, novel treatments. To that end, we clinically tested an autologous T-cell product that targets multiple tumor-associated antigens (TAAs) expressed by lymphomas with the intent of treating disease and preventing immune escape.

Patients and methods: We expanded polyclonal T cells reactive to five TAAs: PRAME, SSX2, MAGEA4, SURVIVIN, and NY-ESO-1. Products were administered to 32 patients with Hodgkin lymphomas (n = 14) or non-Hodgkin lymphomas (n = 18) in a two-part phase I clinical trial, where the objective of the first phase was to establish the safety of targeting all five TAAs (fixed dose, 0.5 × 107 cells/m2) simultaneously and the second stage was to establish the maximum tolerated dose. Patients had received a median of three prior lines of therapy and either were at high risk for relapse (adjuvant arm, n = 17) or had chemorefractory disease (n = 15) at enrollment.

Results: Infusions were safe with no dose-limiting toxicities observed in either the antigen- or dose-escalation phases. Although the maximum tolerated dose was not reached, the maximum tested dose at which efficacy was observed (two infusions, 2 × 107 cells/m2) was determined as the recommended phase II dose. Of the patients with chemorefractory lymphomas, two (of seven) with Hodgkin lymphomas and four (of eight) with non-Hodgkin lymphomas achieved durable complete remissions (> 3 years).

Conclusion: T cells targeting five TAAs and administered at doses of up to two infusions of 2 × 107 cells/m2 are well-tolerated by patients with lymphoma both as adjuvant and to treat chemorefractory lymphoma. Preliminary indicators of antilymphoma activity were seen in the chemorefractory cohort across both antigen- and dose-escalation phases.

Trial registration: ClinicalTrials.gov NCT01333046.

Conflict of interest statement

Spyridoula Vasileiou

Consulting or Advisory Role: AlloVir

Premal Lulla

Stock and Other Ownership Interests: Johnson & Johnson (I)

Ifigeneia Tzannou

Stock and Other Ownership Interests: AlloVir

Ayumi Watanabe

Consulting or Advisory Role: AlloVir

Manik Kuvalekar

Consulting or Advisory Role: AlloVir

Mrinalini Bilgi

Employment: Carsgen Therapeutics Ltd

Carlos Ramos

Consulting or Advisory Role: Novartis

Research Funding: Tessa Therapeutics, Kuur Therapeutics (Inst)

Rayne Rouce

Honoraria: Novartis Pharmaceuticals UK Ltd, Kite/Gilead

Research Funding: Tessa Therapeutics (Inst)

Bambi Grilley

Employment: South Texas Nuclear Pharmacy (I), Q B Regulatory Consulting

Leadership: AlloVir

Stock and Other Ownership Interests: AlloVir

Travel, Accommodations, Expenses: Tessa Therapeutics

Juan Vera

Employment: Marker Therapeutics

Leadership: Marker Therapeutics, AlloVir

Stock and Other Ownership Interests: Marker Therapeutics, AlloVir

Consulting or Advisory Role: Marker Therapeutics, AlloVir

Research Funding: Marker Therapeutics

Patents, Royalties, Other Intellectual Property: I am an inventor in patents license to Marker Therapeutics Inc and Allovir. Marker Therapeutics Inc is currently advancing a T cell therapy in AML while Allovir is developing T cell therapies for viral infections.

Travel, Accommodations, Expenses: Marker Therapeutics, AlloVir

Catherine Bollard

Leadership: Mana Therapeutics, Cabaletta Bio, Catamaran Bio

Stock and Other Ownership Interests: Mana Therapeutics, Neximmune, Torque, Caballeta Bio, Catamaran Bio

Consulting or Advisory Role: Torque, NexImmune, Cellectis, Cabaletta Bio

Patents, Royalties, Other Intellectual Property: TAA-specific T cells and HIV specific T cells

Open Payments Link

https://openpaymentsdata.cms.gov/physician/381202

Malcolm Brenner

Stock and Other Ownership Interests: Bluebird Bio, Tessa Therapeutics, Maker Therapeutics, AlloVir, Walking Fish, Allogene Therapeutics, Memgen, KURR, Bellicum Pharmaceuticals, TScan Therapeutics, Poseida Therapeutics, Abintus

Honoraria: Merck (I)

Consulting or Advisory Role: Tessa Therapeutics, Memgen, Torque, NantWorks, Poseida Therapeutics, Cell Medica (I), Formula Pharmaceuticals, Walking Fish Therapeutics, TScan Therapeutics, Alimera Sciences, Maker Therapeutics, Turnstone Bio

Research Funding: Cell Medica (I)

Patents, Royalties, Other Intellectual Property: Not applicable because it's not related.

Travel, Accommodations, Expenses: Merck (I), Tessa Therapeutics, Bluebird Bio, Torque

Helen Heslop

Stock and Other Ownership Interests: Marker Therapeutics, AlloVir

Consulting or Advisory Role: Gilead Sciences, Novartis, Kiadis Pharma, Tessa Therapeutics, Marker Therapeutics, PACT Pharma, Mesoblast

Research Funding: Cell Medica (Inst), Tessa Therapeutics (Inst)

Cliona Rooney

Leadership: Tessa Therapeutics (I)

Stock and Other Ownership Interests: Marker Therapeutics, Marker Therapeutics (I), Bluebird Bio (I), Allovir, Allovir (I)

Consulting or Advisory Role: Tessa Therapeutics, Tessa Therapeutics (I), Alimera Sciences (I), Memgen (I), TScan Therapeutics (I)

Research Funding: Tessa Therapeutics

Patents, Royalties, Other Intellectual Property: Takeda, Allogene, Bellicum

Travel, Accommodations, Expenses: Tessa Therapeutics, Tessa Therapeutics (I)

Ann Leen

Stock and Other Ownership Interests: Marker Therapeutics, Allovir

Consulting or Advisory Role: Marker Therapeutics, Allovir

Patents, Royalties, Other Intellectual Property: I have patents and pending patents in the field of cell therapy and I have received royalty payments.

Travel, Accommodations, Expenses: Allovir

No other potential conflicts of interest were reported.

Figures

FIG 1.

Characterization of autologous multiple tumor-associated antigen–T cells. (A) Fold expansion, (B) phenotype, and (C) memory and activation profile of mTAA–T-cell lines. (D) TAA-directed specificity as measured by enzyme-linked immune absorbent spot for 32 products generated using all five antigens as a stimulus. Data are shown as spot-forming cells (SFCs) ± SEM, and each color represents an individual antigenic specificity. (Ε) Lack of in vitro multiple tumor-associated antigen–T-cell cytolytic activity against autologous (nonmalignant) targets at an effector to target ratio of 20:1.

FIG 2.

Clinical outcomes of infused patients. Swimmers plots depicting outcomes after infusion in patients with (A) HL and (B) NHL. Those who were in remission at the time of infusion in each group are labeled adjuvant, and those who had active lymphoma at the time of infusion are labeled as active disease. Those who were infused on the antigen-escalation phase of the study are indicated. HL, Hodgkin lymphomas; NHL, non-Hodgkin lymphomas.

FIG 3.

In vivo behavior of multiple tumor-associated antigen–T cells. Expansion of T cells specific for targeted tumor-associated antigens and other nontargeted tumor-associated antigens in patients with active disease versus those infused as (A) adjuvant; (B) patients with HL vs those with NHL; and (C) responders (defined as continued complete remission and complete remission) versus nonresponders. Results are reported as log-transformed fold expansion values (mean ± SEM) by week 6 after infusion. Statistical significance was assessed by t-test for continuous variables. **Denotes statistical significance. HL, Hodgkin lymphomas; n.s., nonsignificant; NHL, non-Hodgkin lymphomas.