Development of complehensive cancer immune cell therapies to overcome immune tolerance

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08615
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Mekata Eiji 滋賀医科大学, 医学部, 教授 (80314152)
• Co-Investigator(Kenkyū-buntansha): 村田 聡 滋賀医科大学, 医学部, 講師 (90239525) ; 三宅 亨 滋賀医科大学, 医学部, 講師 (70581924) ; 谷 眞至 滋賀医科大学, 医学部, 教授 (60236677)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 免疫寛容 / 抗腫瘍免疫 / 複合的免疫療法 / OX40 / LAP / PD-1 / PD-L2

Outline of Final Research Achievements

We conducted this research to establish a cancer antigen-specific CTL therapy that can overcome immune tolerance using the removal of TGF-β-producing immunosuppressive cells by LAP adsorption column, the function of CTL enhancing and regulatory T cell function inhibiting effects by OX40 costimulation, T cell costimulatory function by mB7-DC-Fc, or, the immune checkpoint inhibitory effect by PD-1 blocker.
CTL induction in an immunosuppressive cell-removed environment was effective. When LAP-T cells were induced with cancer antigen-specific CTL under cancer antigen stimulation and OX40-assisted stimulation, the transferred CTL maintained antitumor immune activity even under cancer antigen-specific immune tolerance and rejected the tumor. In addition, CTL induction by B7-DC costimulation or PD-1 inhibition was effective in maintaining CTL function under immune tolerance.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

ペプチドワクチン療法や細胞傷害性Tリンパ球（CTL）移入療法などがヒト癌免疫治療に臨床応用されてきたが、満足のいく臨床成果は得られていない。生体では癌抗原（自己抗原）に対する免疫寛容（トレランス）が働くために、癌抗原特異的CTLを細胞移入しても、生体のトレランス機能に負け、CTLは抗腫瘍作用を失う。したがって、本研究で開発した免疫トレランスを打ち破る方法は、ヒト癌免疫治療を成功へと導く鍵となるであろう。本研究で明らかとなった有効な免疫作用を複合させたCTL誘導により、さらに強力なCTL細胞療法の開発が可能となる。