HORMAD-specific TGF-beta resistant memory T cells for treatment of patients with Gastro-esophageal Cancer
HORMAD 特异性 TGF-β 耐药性记忆 T 细胞用于治疗胃食管癌患者
基本信息
- 批准号:10731407
- 负责人:
- 金额:$ 140.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-19 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAddressAdoptive Cell TransfersAdoptive TransferAdvanced Malignant NeoplasmAffinityAlgorithmsAllelesAntigensBlood CellsBlood specimenCD8-Positive T-LymphocytesCTAG1 geneCell Cycle ProteinsCell TherapyCellsClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyDNA Repair GeneDiseaseDominant-Negative MutationDoseEZH2 geneEffectivenessEffector CellEndowmentEngineeringEpigenetic ProcessEpitope spreadingEpitopesEsophagusFamilyFunctional disorderGene Expression ProfilingGenerationsGenesHLA-A11HLA-A2 AntigenImmunologic Suppressor FactorsImmunologyImmunosuppressionIn VitroInfusion proceduresLungMalignant NeoplasmsMalignant neoplasm of esophagusMalignant neoplasm of pancreasMalignant neoplasm of urinary bladderMediatingMemoryModalityOutcomeOvarianPatientsPeptidesPhasePhase Ib Clinical TrialPhenotypePopulationPrevalenceProductionProliferatingPropertyProteinsProtocols documentationRegulatory T-LymphocyteResistanceSafetySamplingSolid NeoplasmSourceSpecificityStomachSurfaceT cell differentiationT cell therapyT memory cellT-LymphocyteT-Lymphocyte SubsetsTGFBR2 geneTestisTissuesToxic effectTransforming Growth Factor betaTransforming Growth Factor beta ReceptorsTumor AntigensTumor Suppressionantigen-specific T cellsarmcancer/testis antigencohortcytokinecytotoxicityengineered T cellsepigenetic memoryepigenetic profilingepigenomicsexhaustionfirst-in-humanflexibilitygastroesophageal cancergp100 Antigenimmune resistanceimmunogenicimmunogenicityin silicoin vivoinhibitorinterleukin-21malignant stomach neoplasmmanufacturemelanocytemortalitynovelperipheral bloodpharmacologicprogramsprotocol developmentrational designresponseretroviral transductionself-renewalsingle-cell RNA sequencingsuccesstargeted treatmenttranscriptomicstumortumor microenvironment
项目摘要
Project Summary
This proposal addresses three major challenges in adoptive cellular therapy: 1) T cell persistence; 2) Tumor
immune resistance and 3) Target epitope identification for solid tumors, bringing together the expertise of Dr.
Yee in T cell therapy, Dr. Rai in epigenetics and Dr. Morelli in clinical trials. We have established a strategy for
generating memory T cells from peripheral blood of patients, via an ACT modality known as Endogenous T Cell
(ETC) therapy pioneered in the Yee lab, allowing us to target HORMAD1, a cancer testis antigen broadly
expressed in gastric and esophageal cancer, which in its advanced stages represents a significant unmet need.
By applying rationally designed combinations of epigenetic modulators we plan to optimize the replicative
capacity and memory properties of HORMAD1-specific CTL (HMD-CTL) generate ex vivo to address the
challenge of limited in vivo T cell persistence (UG3 Aim 1). One of the dominant extrinsic factors mediating tumor
immune resistance in gastric and esophageal cancer is the influence of TGF-β in the tumor microenvironment.
In addressing this challenge, we propose the use of a dominant negative TGF-β receptor to sequester TGF-β by
engineering expression of the TGFBDNR2 gene into HORMAD1-specific CTL using a retroviral transduction
strategy that is well-established in the Cell Therapy Manufacturing Center (UG3 Aim 2). Finally, addressing the
challenge of targeting gastric and esophageal cancers was borne out of an ongoing antigen discovery pipeline
developed over 5 years examining the portfolio of tandem mass spectrometric defined epitopes eluted from MHC
of over 30 tumor samples. From this pipeline we have empirically validated both an HLA-A2 and HLA-A11
epitopes of HORMAD1, demonstrated high affinity with CTL generated using the ETC workflow and propose the
use of HORMAD1-specific CTL for this trial, allowing us to cover more than 25% of all gastric and esophageal
patients given the prevalence of HORMAD1 expression in these tumors (> 40%) and HLA allele expression (>
65%). At completion of the UG3 portion of this proposal, we will identify an optimal epigenetic program (Aim 1)
and TGFBDNR2 transduction workflow (Aim 2) that fulfills the metrics for a Go/ No-Go decision. In the clinical
trial component (UH3) these strategies will be assembled to allow us to evaluate safety and duration of in vivo
persistence, comparing HORMAD1-specific CTL and TGFBDNR2-engineered HORMAD-1-specitic CTL in two
cohorts, while assessing for preliminary efficacy in an Expansion arm.
The ETC platform provides greater flexibility than other ACT modalities in its agility to direct specificity to
almost any desired target epitope, demonstrated evidence of antigen-spreading, minimal toxicities, and has an
established memory potential proven to be sustained in several clinical trials. We anticipate, that with an
enhanced epigenetic memory program and, endowed with a mechanism to undermine at least one feature of
tumor immune resistance, ETC therapy can provide a vehicle for advancing adoptive cellular therapy for the
treatment of solid tumors in a systematic and stepwise fashion.
项目总结
项目成果
期刊论文数量(0)
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Maria Pia Morelli其他文献
Combination of epidermal growth factor receptor inhibitors and antiangiogenic drugs: a model for treatment
- DOI:
10.1007/s11523-006-0022-5 - 发表时间:
2006-05-19 - 期刊:
- 影响因子:4.000
- 作者:
Erika Martinelli;Teresa Troiani;Floriana Morgillo;Maria Carmela Piccirillo;Katia Monaco;Maria Pia Morelli;Tina Cascone;Fortunato Ciardiello - 通讯作者:
Fortunato Ciardiello
A pilot study of the PD-1 targeting agent AMP-224 combined with low-dose cyclophosphamide and stereotactic body radiation therapy in patients with metastatic colorectal cancer
PD-1靶向剂AMP-224联合小剂量环磷酰胺和立体定向体部放射治疗转移性结直肠癌的初步研究
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
C. Floudas;Gagandeep Brar;Donna Mabry;A. Duffy;Bradford J Wood;Elliot Levy;V. Krishnasamy;S. Fioravanti;M. Cecilia;Bonilla;M. Walker;Maria Pia Morelli;D. E. Kleiner;S. M. Steinberg;William;D. Figg;T. F. Greten;Changqing Xie - 通讯作者:
Changqing Xie
Correction: First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors
- DOI:
10.1186/s13046-023-02668-3 - 发表时间:
2023-04-26 - 期刊:
- 影响因子:12.800
- 作者:
Christopher B. Cole;Maria Pia Morelli;Massimo Fantini;Markku Miettinen;Patricia Fetsch;Cody Peer;William D. Figg;Tyler Yin;Nicole Houston;Ann McCoy;Stanley Lipkowitz;Alexandra Zimmer;Jung-min Lee;Miroslava Pavelova;Erin N. Villanueva;Kathryn Trewhitt;B. Brooke Solarz;Maria Fergusson;Sharon A. Mavroukakis;Anjum Zaki;Kwong Y. Tsang;Philip M. Arlen;Christina M. Annunziata - 通讯作者:
Christina M. Annunziata
Maria Pia Morelli的其他文献
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