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Overview
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Overview

Immuno-oncology (IO) focuses on exploiting the immune system to elicit appropriate anti-tumor responses and to block the progression of cancer. The immune system is naturally equipped with defense mechanisms to prevent invasion by pathogens. Immunological checkpoints, such as programmed cell death protein-1 (PD-1) and CTLA-4, are an integral part of the repertoire of checks and balances available in the body for preventing attacks on its own immune cells. Such an ability to discriminate between self and non-self is critical for preventing uncontrolled immune responses. Cancer cells and the tumor microenvironment, however, can adopt these immunological checkpoints to pose as “self” molecules and evade the natural defense of the body’s own immune system. Tumor cells can express the PD-1 ligand (PD-L1) on their surface to bind with PD-1 and activate this brake or off-switch of the immune system. Immuno-oncology approaches involve breaking this manipulation of immune checkpoint proteins by using inhibitors (e.g., anti-PD-1/PD-L1 agents) to block PD-1/PD-L1 interaction and allow the recognition of tumor cells by the immune system.1 Combining immunotherapy with other standard of care options, such as surgery, radiotherapy and chemotherapy, has also been adopted recently.

performance1

Tumor microenvironment

The tumor microenvironment (TME), which includes blood and lymph vessels and mesenchymal and immune cells, is a major contributor to tumor progression and therapy outcome. TME characteristics have been linked to response or resistance to therapy with high infiltration of cytotoxic T cells supporting a better immune response to attack tumor cells.2 Modulation of TME is also a strategy used for tumor suppression. T cell-targeted immunomodulators such as monoclonal antibodies against PD-1 or CTLA-4 are used in combination with T cells engineered with chimeric antigen receptor (CAR) (CAR-T cells) against several malignancies in clinical trials.3 The fourth generation of (CAR) design attempts to deliver cytokines to modulate the TME either by activating host effector T cells or hampering host suppressors and reinforcing memory T cells. These cytokine-producing CARs, called T cells redirected for universal cytokine killing (TRUCKs), can deliver a variety of cytokines, such as IL-12, IL-15, IL-18 or IL-21 to control immune effector functions.4

Cancer stem cells

Cancers consist of a heterogeneous cell population with different functions and phenotypes. A proportion of cancer cells with stem cell characteristics, known as cancer stem cells (CSC), have been described in several cancer types including colon, brain, lung, breast, ovarian and blood cancers. CSCs serve as a pool to replenish the tumor core with more differentiated cancer cells and are considered as a source of resistance to conventional cancer therapy (e.g., radiotherapy, chemotherapy) and for tumor relapse. A ratio of CSC:non-CSC in favor of CSC correlates with poor survival.5 CSCs are actively being evaluated as targets in oncology therapy including immuno-oncology therapeutic approaches, such as anti-CD44 antibodies and STAT3 inhibitor VII in breast cancer, tarextumab against Notch 2/3 in small cell lung carcinoma, and myrtucommulone-A and motesanib against PI3K/AKT in bladder cancer.6 According to the 2018 GLOBOCAN study, tumors with the highest mortality rates (e.g., lung, stomach, liver, breast, colorectal cancers) are usually highly heterogeneous and exhibit different extents of stem cell activities.7

References

  1. Wu X, Gu Z, Chen Y, et al. Application of PD-1 blockade in cancer immunotherapy. Comput Struct Biotechnol J. 2019;17:661-674. doi:10.1016/j.csbj.2019.03.006

  2. Shen R, Li P, Li B, Zhang B, Feng L, Cheng S. Identification of distinct immune subtypes in colorectal cancer based on the stromal compartment. Front Oncol. 2020;9:1497. doi:10.3389/fonc.2019.01497

  3. Feins S, Kong W, Williams EF, Milone MC, Fraietta JA. An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am J Hematol. 2019;94(S1):S3-S9. doi: 10.1002/ajh.25418

  4. Knochelmann HM, Smith AS, Dwyer CJ, Wyatt MM, Mehrotra S, Paulos CM. CAR T cells in solid tumors: Blueprints for building effective therapies. Front Immunol. 2018;9:1740. doi: 10.3389/fimmu.2018.01740

  5. Pan Y, Ma S, Cao K, et al. Therapeutic approaches targeting cancer stem cells. J Cancer Res Ther. 2018;14(7):1469-1475. doi:10.4103/jcrt.JCRT_976_17

  6. Shibata M, Hoque MO. Targeting cancer stem cells: a strategy for effective eradication of cancer. Cancers (Basel). 2019;11(5):732. doi:10.3390/cancers11050732

  7. Walcher L, Kistenmacher AK, Suo H, et al. Cancer stem cells-origins and biomarkers: perspectives for targeted personalized therapies. Front Immunol. 2020;11:1280. doi:10.3389/fimmu.2020.01280
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