T cells are a crucial component of the immune response to infection and cancer. In addition to coordinating immunity in lymphoid tissue, T cells play a vital role at the disease site, which relies on their efficient and specific trafficking capabilities. The process of T-cell trafficking is highly dynamic, involving a series of distinct processes, which include rolling, adhesion, extravasation, and chemotaxis. Trafficking of T cells to the tumor microenvironment is critical for the success of cancer immunotherapies such as adoptive cellular transfer. Although this approach has achieved some remarkable responses in patients with advanced melanoma and hematologic malignancy, the success against solid cancers has been more moderate. One of the major challenges for adoptive immunotherapy is to be able to effectively target a higher frequency of T cells to the tumor microenvironment, overcoming hurdles associated with immunosuppression and aberrant vasculature. This review summarizes recent advances in our understanding of T-cell migration in solid cancer and immunotherapy based on the adoptive transfer of natural or genetically engineered tumor-specific T cells and discusses new strategies that may enhance the trafficking of these cells, leading to effective eradication of solid cancer and metastases. Cancer Res; 74(24); 7168–74. ©2014 AACR.

The redirection of T cells against tumors holds much promise for the treatment of cancer. Two main approaches for T-cell redirection involve their genetic modification with chimeric antigen receptors (CAR), or the use of recombinant proteins designated bispecific T-cell engagers (BiTE). These approaches have demonstrated dramatic effects in patients with hematologic cancers, although limited effect against solid cancers. Here, we review and compare the successes and challenges of these two types of immunotherapies, with special focus on their mechanisms, and discuss strategies to improve their efficacy against cancer. Significance: CAR and BiTE cancer therapies have generated much excitement, but although the therapies are potentially competitive, information directly comparing the two is difficult to obtain. Here, we present the fundamentals of each approach and compare the range and level of functions they can elicit from T cells, and their efficacy against cancers. Cancer Discov; 8(8); 1–11. ©2018 AACR.

Recent advances in cancer immunology have led to a better understanding of the role of the tumor microenvironment (TME) in tumor initiation, progression, and metastasis. Tumors can occur at many locations within the body and coevolution between malignant tumor cells and non-malignant cells sculpts the TME at these sites. It has become increasingly clear that there are specific differences of the TMEs at different anatomical locations, and these tissue-specific TMEs regulate tumor growth, determine metastatic progression, and impact on the outcome of therapy responses. Herein, we review the scientific advances in understanding tissue-specific TMEs, discuss their impact on immunotherapeutic response, and assess the current clinical knowledge in this emerging field. A deeper understanding of the tissue-specific TME will help to develop effective immunotherapies against tumors and their metastases and assist in predicting clinical outcomes.

Patients who receive chimeric antigen receptor (CAR)–T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8 ⁺ memory T cell progenitors that can become either functional stem-like T (T _STEM ) cells or dysfunctional T progenitor exhausted (T _PEX ) cells. To that end, we demonstrated that T _STEM cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients. To address this issue, we developed a production protocol to generate T _STEM -like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, T _STEM -like CAR-T cells had enhanced proliferative capacity and increased cytokine secretion after CAR stimulation, including after chronic CAR stimulation in vitro. These responses were dependent on the presence of CD4 ⁺ T cells during T _STEM -like CAR-T cell production. Adoptive transfer of T _STEM -like CAR-T cells induced better control of established tumors and resistance to tumor rechallenge in preclinical models. These more favorable outcomes were associated with increased persistence of T _STEM -like CAR-T cells and an increased memory T cell pool. Last, T _STEM -like CAR-T cells and anti–programmed cell death protein 1 (PD-1) treatment eradicated established tumors, and this was associated with increased tumor-infiltrating CD8 ⁺ CAR ⁺ T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated T _STEM -like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.

Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model. Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors. Results: ACTIV therapy induced durable complete remission of a variety of Her2⁺ tumors, some in excess of 150 mm², in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient. Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues. Clin Cancer Res; 23(10); 2478–90. ©2016 AACR.

Rapid advances in immunotherapy have identified adoptive cell transfer as one of the most promising approaches for the treatment of cancers. Large numbers of cancer reactive T lymphocytes can be generated ex vivo from patient blood by genetic modification to express chimeric antigen receptors (CAR) specific for tumor-associated antigens. CAR T cells can respond strongly against cancer cells, and adoptive transferred CAR T cells can induce dramatic responses against certain types of cancers. The ability of T cells to respond against disease depends on their ability to localize to sites, persist and exert functions, often in an immunosuppressive microenvironment, and these abilities are reflected in their phenotypes. There is currently intense interest in generating CAR T cells possessing the ideal phenotypes to confer optimal antitumor activity. In this article, we review T cell phenotypes for trafficking, persistence and function, and discuss how culture conditions and genetic makeups can be manipulated to achieve the ideal phenotypes for antitumor activities.