Neoantigens derived from tumor-associated mutations can elicit T cell-mediated antitumor immunity and facilitate tumor rejection. Here, we assessed the safety and efficacy of personalized neoantigen peptide vaccination (PPV) in advanced NSCLC patients who had failed conventional therapy.
24 stage III/IV recurrent NSCLC patients were immunized with mixtures of short and long neoantigen peptides based on personalized tumor-associated mutations and predicted HLA peptide binding affinities. Primary study endpoints were feasibility and safety. Secondary endpoints were PPV-induced immune responses, progression-free survival (PFS) and overall survival (OS).
Aside from transient rash, fatigue and/or fever in 3 patients, no treatment-related adverse events were observed. The median PFS and OS of the 24 PPV patients was 6.0 and 8.9 months, respectively. Of the 16 PPV patients bearing EGFR mutations, 7 experienced objective tumor response by RECIST 1.1, including 6 PR and 1 CR. Of the 8 patients expressing wild-type EGFR, 4 showed SD and no PR or CR. Importantly, 9 PPV patients who continued EGFR inhibitor (EGFRi) therapy in spite of prior progression showed extended survival compared to 7 patients who stopped EGFRi prior to initiating PPV (median OS: 13.8 vs. 7.6 months, P = 0.038), though both patient groups experienced similar objective response rates. Immune monitoring demonstrated the immunogenicity of two highly shared EGFR mutations in multiple responding patients. Robust PPV-specific immune responses were observed in 4 responding patients, with ELISPOT and tetramer staining showing incremental increases in peripheral blood neoantigen-specific CD8+ T cell frequencies for up to 3 months during PPV. T-cell receptor (TCR) Vb sequencing also demonstrated significantly increased frequencies of neoantigen-specific CD8+ TCR clones in both peripheral blood and tumor-infiltrating lymphocytes following PPV.
These results suggest that PPV is safe and potentially beneficial for advanced stage EGFR-mutated NSCLC patients. Survival analyses imply that PPV in combination with EGFRi may be a viable treatment option for NSCLC, in spite of prior EGFRi failure.
ChiCTR-INR-16009867.
Tianjin Beichen Hospital.
Tianjin HengJia Biotechnology Development Co., Ltd.
F. Li: Shareholder / Stockholder / Stock options: Tianjin HengJia Biotechnology Development Co., Ltd. G. Lizee: Advisory / Consultancy: HengJia Neoantigen Biotechnology (Tianjin) Co., Ltd. P. Hwu: Advisory / Consultancy: Dragonfly Therapeutics; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Immatics; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Genentech. L. Deng: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. Q. Zou: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. M.A. Stairs: Advisory / Consultancy: HengJia Neoantigen Biotechnology (Tianjin) Co., Ltd. C. Chen: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. C. Huo: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. Y. Wang: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. All other authors have declared no conflicts of interest.
Tumor-specific neoantigens provide personalized targets for immunotherapy. Vaccines against epitopes predicted by in silico approaches very rarely induce CD4+ and CD8+ ex vivo T cell responses regardless of formulation. ATLAS selects neoantigens for vaccine inclusion using ex vivo screening of all patient-specific mutations to identify pre-existing CD4+ or CD8+ T cell responses and to exclude inhibitory peptides that suppress immunity and accelerate tumor progression. Preliminary data suggest that the inhibitory peptide profile may predict tumor response to immunotherapy.
GEN-009-101 is a phase I/IIa study testing safety, immunogenicity and clinical activity in immune responsive tumors. After next-generation tumor sequencing and ATLAS testing of autologous leukocytes, up to 20 stimulatory synthetic long peptides adjuvanted with poly-ICLC make each personalized vaccine. The immunogenicity pilot has enrolled 9 patients in remission to receive GEN-009 monotherapy.
4 patients have participated to the primary immunogenicity readout at day 50 (some data pending). The 17 doses given across patients have induced only mild local discomfort and no DLT. ATLAS results show high interpatient variability. Vaccination has generated immune responses against 94% of administered peptides, and both CD8+ and CD4+ responses in a 44 hr ex vivo fluorospot assay. Ten-day in vitro stimulation (IVS) assays result in broader immune responses. 1178PD number of positive peptides/total peptides immunizedPT Tumor Type Somatic Mutations/Mb ATLAS Neoantigens Post-vaccination Response* Stimulatory Inhibitory ex vivo CD4/CD8 IVS CD4/CD8 Total Positive 1 NSCLC 1.25 6 0 10% / 40% 100% / 20% 100% 2 Bladder 3.15 16 4 50% / 38% 63% / 50% 88% 3 Melanoma 28.69 199 41 6% / 38% 75% / TBD TBD 4 Bladder 3.53 18 1 TBD TBD TBD 5 NSCLC 3.56 16 9 55% / 45% TBD TBD
GEN-009 is a neoantigen vaccine that identifies tumor specific immune targets from the individual patient’s repertoire. Immunogenicity data show that ATLAS can, with very high frequency, identify relevant neoantigens and exclude suppressive peptides. Clinical vaccination with PD-1 blockade is in process.
NCT03633110, issued 6-Aug-2018.
Genocea Biosciences.
Genocea Biosciences.
P. Twardowski: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy: Bristol-Myers Squibb. M.L. Johnson: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech / Roche; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Mirati; Advisory / Consultancy, Research grant / Funding (institution): LOXO; Advisory / Consultancy: Calithera; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Araxes Pharma; Advisory / Consultancy: Mersana Therapeutics ; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Incyte; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Guardant Health; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Ribon Therapeutics ; Research grant / Funding (institution), Travel / Accommodation / Expenses: AbbVie; Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution), Travel / Accommodation / Expenses, Spouse / Financial dependant: Clovis; Spouse / Financial dependant: Otsuka Pharmaceuticals; Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): Stemcentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Array Biopharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Neovia; Research grant / Funding (institution): Hengrui Therapeutics, INC; Research grant / Funding (institution), Travel / Accommodation / Expenses: Daiichi - Sankyo; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): Cytomx; Research grant / Funding (institution): Birdie; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): Genocea; Research grant / Funding (institution): Gritstone; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Kadmon; Research grant / Funding (institution): Acerta; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Shattuck Labs; Research grant / Funding (institution): GlaxoSmithKline; Travel / Accommodation / Expenses: Exelixis; Travel / Accommodation / Expenses: Sysmex Inostics; Travel / Accommodation / Expenses: Vapotherm. M. Stein: Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy: Exelixis; Research grant / Funding (institution): Oncoceutics; Research grant / Funding (institution): Janssen Oncology; Research grant / Funding (institution): Medivation/Astellas; Research grant / Funding (institution): Advaxis; Research grant / Funding (institution): Suzhou Kintor Pharmaceuticals; Research grant / Funding (institution): Harpoon; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genocea; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Xencor. M.L. Gillison: Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Aspyrian; Advisory / Consultancy: Celgene; Advisory / Consultancy: Britsol-Myers Squibb; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Genocea; Advisory / Consultancy: Lilly; Advisory / Consultancy: NewLink; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ventana; Advisory / Consultancy: Biomimetix. L. McNeil: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. L. Dowal: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. D. DeOliveira: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. M. Jain: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. J. Price: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. R. Hernandez: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. A. DeCillis: Advisory / Consultancy: Genocea; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Exelixis; Advisory / Consultancy: Pyramid; Advisory / Consultancy: Daiichi Sankyo. N. Singh: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Genocea. T. Davis: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Genocea. J. Flechtner: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Genocea. R.B. Cohen: Advisory / Consultancy, Research grant / Funding (institution): Genocea; Advisory / Consultancy, Research grant / Funding (institution): Innate Biopharma; Advisory / Consultancy, Research grant / Funding (institution): HEAT Biologics; Advisory / Consultancy: Cantargia; Advisory / Consultancy: Tmunity; Research grant / Funding (institution): Arrys; Research grant / Funding (institution): Celldex. All other authors have declared no conflicts of interest.
Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived myeloid and plasmacytoid dendritic cells (mDCs and pDCs).
In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity (DTH)-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and OS. Radiological responses were assessed by regular as well as ferumoxtran-10 enriched MRI and 68Ga-PSMA PET/CT scans according to RECIST 1.1, PCWG2 criteria and immune-related response criteria.
Both tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) DTH-skin test-derived antigen specific T cells were present more frequently in patients with radiological non-progressive disease compared to progressive patients (5/13 (38%) vs. 0/8 (0%)). In dm+ and IFN-γ+ patients median rPFS was 18.8 months vs. 5.1 months in patients without IFN-γ+ antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1-2 toxicity. Immunological outcomes and clinical correlates will be presented.
Immunotherapy with primary DC subsets induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with longer rPFS.
NCT02692976.
Jolanda de Vries and Winald Gerritsen.
This work was supported by Stichting Afweer Tegen Kanker, Dr. Paul A.J. Speth Stichting and H2020 EU grant PROCROP (grant No 635122). Carl G. Figdor received ERC Adv Grant PATHFINDER (269019) and the NWO Spinoza grant. I. Jolanda M. de Vries received NWO-Vici grant (918.14.655).
All authors have declared no conflicts of interest.
Application of monoclonal antibodies (mAbs) as immune checkpoint inhibitors (ICIs) has demonstrated remarkable activity in cancer immunotherapy. Active immunization with mimotopes (B cell epitopes) of ICIs rather than application of the corresponding mAbs for passive immunotherapy may, however, provide advantages such as induction of antibodies by the patient’s own immune system and overcoming the costly treatment of the mAbs.
An established platform involving bacterial surface-display of overlapping peptides spanning the extracellular domains of human/mouse PD1 (h/mPD1), as well as in vitro assays based on T cells expressing h/mPD1 and h/mPDL1, were applied to identify and characterize mimotopes of an anti-human PD1 mAb as well as an anti-mouse PD1 mAb (as a proof of principle).
The PD1-mimotopes were shown to specifically inhibit the binding of the corresponding mAbs and also the mAbs capacity in blocking the respective PD1-PDL1 interactions. Applying a syngeneic mouse model with human Her-2/neu-expressing tumors, a significant tumor growth reduction by passive immunization with specific rabbit IgG against the mPD1-derived mimotope, comparable to the corresponding mAb, was shown. More importantly, active immunization with the mPD1-mimotope resulted in a significant tumor growth reduction associated with a marked increase of PD1 expressing lymphocytes in the tumors. Furthermore, a 68% homology between hPD1 and mPD1 sufficiently facilitated a significant induction of tumor growth reduction in the mice also by IgG against hPD1-derived mimotopes.
Our results demonstrate in vivo anti-tumor effect following active immunization with PD1-derived mimotope in syngeneic mice with tumors expressing human Her-2/neu, implying the use of ICIs mimotopes for cancer immunotherapy. Evaluation of efficacy and safety of our second generation of anti-Her-2/neu vaccine (HerVAXX; Tobias et al, 2017, BMC Cancer) in combination with mimotopes of ICIs as adjuvants is now being carried out. Use of ICI mimotopes may, thus, pave the way for construction of monovalent as well as polyvalent vaccines in combination with tumor specific antigens against different malignancies.
Medical University of Vienna and Ursula Wiedermann.
The study was supported by the Medical University of Vienna and by a research grant from Imugene (Australia) to the Medical University of Vienna.
M. Preusser: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Gerson Lehrman Group; Honoraria (self), Advisory / Consultancy: CMC Contrast; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Mundipharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Medahead; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dome; Research grant / Funding (institution): Böhringer-Ingelheim. C.C. Zielinski: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): MSD; Honoraria (self), Advisory / Consultancy, Scientific Advisory Board member, Until June 2018: Imugene; Honoraria (self), Advisory / Consultancy: Ariad; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): Pfizer; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Merck KGaA; Honoraria (self), Advisory / Consultancy: Fibrogen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Athenex. P. Steinberger: Non-remunerated activity/ies, Reports personal fees from Bristol-Myers Squibb outside the submitted work: Bristol-Myers Squibb. U. Wiedermann: Officer / Board of Directors, CSO, until Sept 2018: Imugene; Research grant / Funding (institution): Phizer; Research grant / Funding (institution): GSK ; Research grant / Funding (institution): Themis. All other authors have declared no conflicts of interest.
The current challenge in developing effective cancer vaccines is the accurate prediction of epitopes that induce CD8+ cytotoxic T-cell responses. Recent technological advances have enabled development of patient-specific therapeutic vaccines. However, in these vaccines only about 10-20% of the predicted neoepitopes induced CD8+ T-cell responses in patients. To overcome this limitation, we developed PASCal for improved selection of peptides (epitopes) that induce T-cell responses.
PASCal operates by 3 moduls: (1) a validated epitope database containing 108 true HLA-epitope pairs derived from 1300 tumor antigens and HLA class I and II molecules covering the HLA genotype of 26000 subjects. (2) Expression frequency-based shared tumor antigen database established for 19 indications based on > 96000 tumor biopsies. (3) Algorithm for the dentification of immunogenic peptides by the selection of personal epitopes (PEPIs) binding to ≥ 3 autologous HLA alleles. Using PASCal, personal 20mer peptide vaccines were designed for 3 HLA-genotyped cancer patients (with ovarian-, breast- and colorectal cancer). Immunogenicity of the vaccines was tested by ELISPOT and Intracellular Citokine Staining (ICS).
Personalized cancer vaccines contained PEPIs from 12 disease specific tumor-antigens most frequently expressed in the patients disease. T-cell responses were induced by 100% of peptides. An average of 11/12 PEPIs induced CD8+ T-cell responses and 12/12 induced CD4+ T-cell responses in each patient. Pre-existing antigen specific T-cell reactivities were detectable against 25% of vaccine antigens (demonstrating the expression of the target vaccine antigens by the patient’s tumor), the others were induced de novo. Both CD8+ and CD4+ T-cells were polyfunctional, as evident by secretion of multiple cytokines determined by ex vivo ICS.
We used the largest validated database of tumor epitopes reported to-date along with an algorithm successfully selecting immunogenic peptides to develop personalized cancer vaccines. PEPIs outperform reported immunogenicity of personalized neoantigen vaccines and induced unprecedented immune responses in cancer patients.
The authors.
Has not received any funding.
E. Somogyi: Shareholder / Stockholder / Stock options: Treos Bio Ltd. Z. Csiszovszki: Shareholder / Stockholder / Stock options: Treos Bio Ltd. O. Lorincz: Shareholder / Stockholder / Stock options: Treos Bio Ltd. J. Toth: Shareholder / Stockholder / Stock options: Treos Bio Ltd. L. Molnar: Shareholder / Stockholder / Stock options: Treos Bio Ltd. W. Schönharting: Shareholder / Stockholder / Stock options: PMCR GmbH. S. Urban: Shareholder / Stockholder / Stock options: PMCR GmbH. K. Pántya: Shareholder / Stockholder / Stock options: Treos Bio Ltd. M. Megyesi: Shareholder / Stockholder / Stock options: Treos Bio Ltd. E.R. Tőke: Shareholder / Stockholder / Stock options: Treos Bio Ltd.; Leadership role: Treos Bio Zrt. All other authors have declared no conflicts of interest.
Adoptive transfer of TCR-redirected T cells has been reported to exhibit efficacy in some patients with melanoma and sarcoma. However, cytokine release syndrome (CRS) or its relations to tumor response has not been well documented. This study aimed to evaluate clinical responses in association with the cell kinetics and CRSs after transfer of high-affinity NY-ESO-1 TCR-gene transduced T cells in cancer patients.
We developed a novel-type affinity-enhanced NY-ESO-1-specific TCR and an originally-developed retrovirus vector that encodes siRNA to silence endogenous TCR creation. The NY-ESO-1/TCR sequence was mutated for high affinity with replacements of G50A and A51E in CDR2 region. This is a first-in-human clinical trial of the novel NY-ESO-1-specfic TCR-T cell transfer to evaluate the safety, in vivo cell kinetics and clinical responses. It was designed as a cell-dose escalation from 5 x108 to 5 x109 cells. NY-ESO-1-expressing refractory cancer patients were enrolled, with 3 + 3 cohort design. Cyclophosphamide (1,500mg/m2) were administered prior to the TCR-T cell transfer as pre-conditioning.
Nine patients were treated with the TCR-T cells that expanded in peripheral blood with a dose-dependent manner, associated with rapid proliferation within 5 days after infusion. Three patients receiving 5x109 cells developed early-onset CRSs, with elevated levels of serum IL-6, IFN-γ. The CRSs on day1 or 2 were well managed with tocilizumab treatment. Three synovial sarcoma patients exhibited tumor shrinkage and partial responses, and they all had high-expression of NY-ESO-1 in the tumor samples, namely, 75% or more. Exploratory analysis revealed that multiple chemotactic cytokines including CCL2 and CCL7, and IL-3 increased in the serum from the patients with CRS. The proportions of effector-memory phenotype T cells in the infused cell-product were significantly associated with CRS development.
The affinity-enhanced NY-ESO-1/TCR-T cell transfer exhibited early-onset CRS in association with in vivo cell proliferation and sequential tumor responses in the patients with high-NY-ESO-1-expressing synovial sarcoma.
NCT02366546.
The authors.
Japan Agency for Medical Research and Development.
All authors have declared no conflicts of interest.
We are conducting a single site, investigator-initiated Phase Ib study with TBI-1301 where autologous T cells are genetically engineered to express a high affinity NY-ESO-1-specific T cell receptor (TCR) and adoptively transferred to HLA-A*02:01+ or A*02:06+ patients with NY-ESO-1+ solid tumors. Point-of-care manufacturing was performed where peripheral lymphocytes are transduced with the MS3II-NY-ESO1-SiTCR retroviral vector, which encodes an exogenous NY-ESO-1 specific TCR and siRNAs targeting endogenous TCR.
Patients underwent modest lymphodepletion with cyclophosphamide (750 mg/m2 on day -3 and -2) followed by a planned infusion of 5x10^9 manufactured TBI-1301 cells on day 0. All patients underwent immune assessment of PBMC by flow cytometry analysis to monitor persistence and phenotype changes of the infused T cells using NY-ESO1-specific pentamer and the following antibodies: CD45RA, HLA-DR, CD27, CD57, CCR7, PD-1, 4-1BB, CD28, TIGIT, CTLA-4, CD103, LAG3, Ki-67, CD25, CD127, and FoxP3.
9 patients (1 endometrial cancer, 1 ovarian cancer, 4 synovial sarcoma, 3 melanoma) were infused with TBI-1301 at the target cell dose with the exception of one synovial sarcoma patient who received 2.1x10^9 TBI-1301 cells. TBI-1301 was well tolerated, and there were no dose limiting toxicities. CRS grade 1-2 was experienced by 5 patients, with two patients requiring tocilizumab. RECIST best overall responses to date are as follows: 2 PR, 5 SD, 1 PD, and 1 pending. Three patients showed detectable levels of NY-ESO1-specific T cells in the periphery for greater than 100 days post infusion. Biomarker analysis of persisting NY-ESO-1 pentamer+ TBI-1301 cells in the peripheral blood showed increased expression of CD27, PD-1 and TIGIT. Additionally, patients with a PR showed significantly higher numbers of NY-ESO-1 CD8+ T cells costaining with CD45RA and CCR7.
ACT with TBI-1301 cells is safe and clinically active. Results provided here confirm long-term persistence of gene-engineered T cells with higher frequencies of CD45RA+ CCR7+ CD8+ T cells in responding patients. Detailed biomarker analysis of persisting TBI-1301 cells will be presented.
NCT02869217.
The authors.
Princess Margaret Cancer Foundation, Takara Bio, Inc.
M.O. Butler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GSK; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Adaptimmune; Research grant / Funding (institution): Takara Bio. A.G. Sacher: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca/MedImmune; Advisory / Consultancy: Bayer; Honoraria (self), Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Gritstone Oncology; Honoraria (self): Merck. S. Takahashi: Full / Part-time employment: Takara Bio, Inc. N. Hirano: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties: Takara Bio, Inc. All other authors have declared no conflicts of interest.
Adoptive cell therapy (ACT) with T cell receptor (TCR) gene modified peripheral blood T cells creates large pools of tumor reactive T cells. Based on preclinical validation we have selected a high affinity MART-1-specific TCR for TCR gene therapy in metastatic melanoma (MM). Utilizing a novel GMP production protocol we performed a phase I trial to asses feasibility, safety and efficacy of TCR gene therapy in pts with MM.
HLA-A2*0201+ pts with irresectable stage IIIc/IV melanoma, expressing MART-1 and MHC class I, with no standard treatment options were included. Autologous T cells were isolated via apheresis and transduced with a MP-71 retroviral vector encoding the 1D3HMCys MART-1 TCR and expanded ex vivo in presence of IL-7 and IL-15. Non-myeloablative chemotherapy was given prior to one i.v. infusion of MART-1 TCR transduced T cells in a dose escalating manner after evaluation of adverse events (AEs). Feasibility, safety (CTCAE 4.0) and ORR (RECIST 1.1) were assessed.
Twelve heavily pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma (mUM) pts were treated with MART-1 TCR transduced T cells across 4 dose cohorts. Transduction efficiency was 42-76%. Viability of the cell product was 92.9-98.5%. Pt 1 received 4.56 x 109 MART-1 TCR transduced T cells but died 9 days post infusion due to multiple organ failure. Subsequent pts received 5 x 107 (n = 3; cohort (c) 2), 25 x 107 (n = 2; c3) and 10 x 107 (n = 6; c4) cells. On-target AEs were dose-dependent and included dermatitis (10/11) max grade 3, uveitis (3/11) max grade 2 and ototoxicity (4/11) max grade 3, highest in cohort 3. Four pts (n = 2 c3; n = 2 c4) showed signs of cytokine release syndrome and 3 pts required tocilizumab. Objective PR by RECIST 1.1 was seen in 2 pts (17%), with a DOR of 4.2 (mUM, c4) and 8.4 (c3) months. Persistence of transduced T cells in peripheral blood was correlated with infused cell dose.
Treatment with MART-1 TCR transduced peripheral blood T cells expanded in presence of IL-7 and IL-15 led to severe dose-dependent toxicity with a maximum tolerated dose of 10 x 107 transduced cells. Despite observed responses, toxicity limited further development and use of this MART-1 TCR cellular therapy in MM patients. NCT02654821.
NCT02654821.
Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL).
KWF Kankerbestrijding.
J.H. Beijnen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Modra Pharmaceuticals BV . J.V. van Thienen: Honoraria (institution), Advisory / Consultancy: Pfizer ; Honoraria (institution), Advisory / Consultancy: Novartis. C.U. Blank: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: GSK; Honoraria (self), Advisory / Consultancy: GenMab; Honoraria (self), Advisory / Consultancy: Pierre Fabre ; Research grant / Funding (institution): NanoString. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy: Scenic Biotech; Advisory / Consultancy: Third Rock Ventures; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck KGaA; Shareholder / Stockholder / Stock options: Neogene Therapeutics; Shareholder / Stockholder / Stock options: Scenic Biotech. J.B.A.G. Haanen: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: AZ/MedImmune; Honoraria (institution), Advisory / Consultancy: Roche/Genentech; Honoraria (institution), Advisory / Consultancy: Ipsen; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: Immunocore; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy: Seattle Genetics; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Honoraria (institution), Advisory / Consultancy: Celsius Therapeutics; Honoraria (institution), Advisory / Consultancy: Gadet ; Honoraria (institution), Advisory / Consultancy: GSK. All other authors have declared no conflicts of interest.
CD19-targeted chimeric antigen receptor-T (CAR-T) cells with CD28 or 4-1BB (28z CAR-T and BBz CAR-T) have shown great promise to treat relapsed or refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) and B cell non-Hodgkin lymphoma (B-NHL). However, studies comparing the clinical outcomes of 28z CAR-T versus BBz CAR-T are lacking. Analysis of our previous double-arm clinical study of 28z CAR-T and BBz CAR-T in treatment of r/r B-ALL (18 cases for each arm) revealed that BBz CAR-T showed shorter initial response time, higher tumor-killing capacity, higher overall survival rate, longer persistence, and less severe cytokine release syndrome and neurotoxicity than 28z CAR-T. This study investigated the efficacy and toxicity of both CAR-T types in B-NHL patients.
BBz CAR-T and 28z CAR-T were prepared under identical manufacturing processes. Patients with r/r B-NHL were pre-treated with fludarabine and cyclophosphamide, and infused with 28z or BBz CAR-T. Tumor burden, CAR-T persistence and adverse events were monitored. The CAR-T that induced dose-limiting toxicity in less than one patient was further evaluated based on dose escalation.
Six patients were treated at the dose of 0.75-5 × 105/kg. Both types of CAR-T cells showed similar antitumor efficacies, with a complete response (CR) rate of 67% within three months. Cytokines including interleukin (IL)-6 and IL-10 were increased after CAR-T infusion. The peak levels of IL-6 and IL-10 were much higher in the 28z CAR-T cohort. Severe cytokine release syndrome (CRS), CAR-T cell related encephalopathy syndrome (CRES) (≥ grade 3), and one death occurred in the 28z CAR-T cohort, resulting in the termination of recruitment of this cohort. Six more patients received BBz CAR-T cells at a dose of 1 × 106/kg with one-month CR rate of 83% and only grade 1/2 adverse events.
BBz CAR-T showed similar antitumor activity, but a more favorable safety profile, compared with 28z CAR-T. This study proved the competence of BBz CAR-T in B-NHL therapy, at least under our manufacturing process.
Peking University Cancer Hospital & Institute.
Immunochina Pharmaceuticals Co., Ltd.
All authors have declared no conflicts of interest.