Research Topics

Adoptive immunotherapy is a potentially curative therapeutic option for patients with advanced cancer. Tumor antigen-specific T cells are generated and expanded in vitro, and the antitumor T cells are adoptively transferred into the patient. Patients' derived peripheral blood mononuclear cells (PBMC) are most often used as a T-cell source. Although T cells in the peripheral blood are polyclonal, they are easily transduced with tumor antigen-specific T cell receptor (TCR) or chimeric antigen receptor (CAR) and efficiently expanded by anti-CD3 monoclonal antibody and cytokines (Fig. 1). Antitumor T cells can also be obtained by tumor-infiltrating lymphocytes (TIL) in certain types of cancer. Recent studies have already shown that CAR-T cell therapy is highly effective for several types of hematologic malignancies (Maude et al. N Engl J Med 2018;, Locke et al. Lancet Oncol 2019; Munshi et al. N Engl J Med 2021). However, adoptive therapy of CAR-T cells against solid tumors has not provided satisfactory treatment efficacy. It has also been noted that a substantial number of patients with B-cell malignancies and multiple myeloma suffer from relapse after treatment with the anti-CD19 or BCMA CAR-T cell therapy. In addition to its limitation in the efficacy, we frequently experience serious side effects due to systemic immune response and huge costs required for individual preparation of antitumor T cell grafts. We are currently performing multiple projects to solve these problems.
Please see the following link for the publication list in our lab.

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Figure 1. Overview of adoptive immunotherapy.

1）T cell modification to enhance its longevity and effector functions

To improve treatment effects of adoptive immunotherapy, we aim to understand and regulate two features acquired by antitumor T cells: differentiation and exhaustion (Fig. 2). Dr. Restifo and colleagues demonstrated that memory T cell differentiation is closely related to persistence of the infused T cells, which is more important than transient effector functions in terms of durable therapeutic efficacy (Gattinoni et al. Nat Med 2011). Although the differentiation of memory T cells inevitably progresses accompanied by T cell proliferation, it can be regulated by modifying specific genes or signaling pathways. We recently reported that genetic ablation of the epigenetic gene PRDM1 (encoding Blimp1) contributes to maintaining an immature memory T cell phenotype: stem cell-like memory T cells (TSCM) and central memory T cells (TCM) during in vitro and in vivo expansion (Yoshikawa et al. Blood 2022).

Another important concept associated with antitumor immunity is T cell exhaustion, which is defined as attenuation of effector functions such as cytokine secretion and proliferative capacity in T cells chronically exposed to the antigenic stimulation. It is now established that blockade of PD-1 successfully reactivates endogenous antitumor T cells in various types of cancer. However, you can also think about why the exhaustion system is equipped in our T cells. It may be required for survival of T cells when they are continuously exposed to the target antigen. In fact, knockout of PD-1 or its regulator TOX does not necessarily result in better control of chronic viral infections or tumor progression in mouse models (Odorizzi et al. J Exp Med 2015; Scott et al. Nature 2019). Fully exhausted T cells acquire unique epigenetic and molecular profiles that cannot be reverted by PD-1 blockade (Pauken et al. Science 2016). These previous studies indicate functional heterogeneity among individual exhausted T cells (Wu et al. Commun Biol 2023). We aim to elucidate these fundamental molecular mechanisms and apply the findings to the development of T cells with durable antitumor effects in any type of cancer.

Figure 2. Functional alteration of antitumor T cells.

2）Control of side effects such as cytokine release syndrome

Adoptive immunotherapy is accompanied by various side effects, in which cytokine release syndrome (CRS) and neurological toxicities are ones of the most frequent and serious complications. These events are induced by cytokines such as IL-6 and IL-1 derived from macrophages (Norelli et al. Nat Med 2018; Giavridis et al. Nat Med 2018). Since the risk for CRS development increases as antitumor response improves, we need to address these adverse events in parallel with therapeutic efficacy. We aim to incorporate a mechanism that attenuates the severity of CRS in antitumor T cells.

3）Development of the system to improve the versatility of cancer immunotherapy

Recent studies have shown that the efficacy of CAR-T cell therapy is highly dependent on the quality of the infused T cells (Fraietta et al. Nat Med 2018). Since antitumor T cell grafts are individually generated by using the patients-derived T cells in most of the cases, heterogeneity of the quality of T cells may result in unstable treatment effects. Huge costs required for individual preparation of the T cell grafts are another problem that hampers widespread use of this therapy. Although the Bispecific T-cell Engager (BiTE) Blinatumomab, which connects the anti-CD3 mAb with the anti-CD19 mAb to confer antileukemic activity to endogenous T cells, has been used in the clinic, its effect seems to be weaker than that induced by the CAR-T cells. We aim to develop "artificial system" that mimics T cell-mediated cytotoxicity applicable to any patient. Successful completion of this project will enable T cell therapy to be a more universal and off-the-self approach.