The Challenges of Novel Therapies in the Care of the Critically Ill Cancer Patient

Cell Proliferation

Cancer occurs as a result of mutations in the signaling pathways that regulate cell turnover, which is usually a tightly regulated process governed by complex interactions between the cell, the extracellular matrix, and circulating cytokines. The broad functional capabilities acquired by cancer cells include autonomous proliferative signaling, replicative immortality, resistance to apoptosis, and induction of angiogenesis.

Cell survival, proliferation, and communication are triggered by ligand binding to cell membrane-bound receptors. Members of the receptor tyrosine kinase superfamily, such as epidermal growth factor receptors (EGFRs), anaplastic lymphoma kinase (ALK), and KIT, are implicitly involved, and are key targets for novel cancer agents. Once a ligand is bound, the intracellular kinase domain initiates effectors via second messenger systems, including the Ras-Raf-MEK-ERK, phosphoinositol-3-kinase (PI3K)/Akt/mTOR, and JAK/STAT pathways. These in turn are regulated by negative feedback mechanisms, including PTEN phosphatase. Examples of mutations and dysregulation at each step have been identified in various cancer subtypes, including induction of growth factor secretion, increased expression of surface tyrosine kinase receptors, and constitutive activation of the intracellular cascade.

Angiogenesis

Under normal conditions, angiogenesis is only transiently active in response to tissue damage and hypoxia. Activation of angiogenesis—the so-called “angiogenic switch”—is a characteristic of tumor growth and metastasis. The key in vivo proangiogenic factor is vascular endothelial growth factor (VEGF), which exerts its effect via a further family of receptor bound tyrosine kinase receptors (VEGFRs).

The Immune Response

The effectors of both the innate and adaptive immune system are critical to tumor growth and suppression. Natural killer (NK) cells are able to induce cell death via apoptosis in the absence of antigen presentation, targeting cells with low expression of major histocompatibility complex (MHC).

The T-cell-mediated adaptive immune response requires priming by antigen presentation in the context of MHC. The T-cell receptor (TCR) has a CD3 domain and highly variable extracellular alpha/beta chains that are generated during T-cell maturation, enabling recognition of a diverse range of antigen. CD8+ T lymphocytes recognize antigen within MHC class I (present on all nucleated cells), whereas CD4+ T lymphocytes recognize antigen within MHC class II (expressed only by specialist antigen presenting cells). On antigen binding, activation is mediated via CD3-associated intracellular messenger systems, leading to cytokine release, and in the case of CD8+ cells, release of perforins.

In order to prevent autoimmunity, mechanisms exist to limit T-cell activation against self-antigens. Activation can only occur in the context of costimulation, regulated by immune checkpoint molecules, which include programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). These proteins, expressed on the surface of CD4+ and CD8+ T-cells, bind programmed cell death 1 ligand (PD-L1) and CD80/CD86 respectively and inhibit cell-mediated apoptosis. Through this mechanism, continued Tcell activation in response to chronic antigen exposure, as occurs with malignancy, leads to downregulation of the response and provides a further route by which tumor cells may escape apoptosis.

Adoptive Cell Transfer

Over the past decades, multiple strategies at adoptive cellular immunotherapy have been trialed. Tumor infiltrating lymphocytes (TILs) are CD8+ T cells that can be isolated from surgical specimens, expanded ex vivo and reinfused, leading to an effective antitumor response, particularly in melanoma. However, TILs cannot be extracted from all tumor types, and as the native TCR requires MHC class I for activation, cytotoxicity can be downregulated or lost entirely when tumor cells do not express MHC class I.

The development of chimeric antigen receptor (CAR)-T cell technology overcomes this limitation. Here, T cells are acquired through peripheral blood culture and are genetically engineered with a CAR via retroviral transduction ( Fig. 40.1 ). This CAR consists of an extracellular domain targeted to a specific tumor marker (e.g., CD19 in B-cell malignancy) linked via a transmembrane hinge protein to the intracellular components of CD3. Second- and third-generation therapies add costimulatory domains such as CD28/CD137 required for T-cell activation. After clonal expansion and reinfusion, CAR-T cells are able to target tumor cells independent of MHC, inciting a potent and persistent antitumor effect.