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.

Chimeric antigen receptor (CAR)-T cell structure.

Targeted Therapies

The first targeted therapy to be licensed was imatinib, a tyrosine kinase inhibitor exerting activity against Bcr-Abl, a mutant constitutively active receptor expressed in Philadelphia chromosome t(9;22) chronic myeloid leukemia. It has since been licensed in t(9;22)-positive acute lymphoblastic leukemia (ALL) and subtypes of gastrointestinal stromal tumors expressing c-Kit.

Other small molecule tyrosine kinase inhibitors have since been developed against a wide range of targets with varying degrees of selectivity. In metastatic non–small cell lung cancer (NSCLC), the first-generation selective EGFR inhibitor erlotinib improved median progression-free survival (PFS) from 5.5 to 11 months when compared against platinum-based chemotherapy. NSCLC expressing anaplastic lymphoma kinase (ALK) fusion oncogene can be treated using ALK inhibitors such as alectinib, which in the ALEX trial, has shown a PFS approaching 3 years. In metastatic clear cell renal cell cancer, the VEGF inhibitor sunitinib versus standard treatment with interferon-alpha was shown to enhance median PFS from 5 to 11 months. On treatment resistance to tyrosine kinase inhibitors is common however, and disease will eventually progress during follow up. Here, second- and third-generation agents may be used (e.g., bosutinib and ponatinib in imatinib resistance, osimertinib in erlotinib resistance) which either exhibit a higher degree of specificity, target multiple proteins, or target a protein further down the intracellular signaling pathway.

Monoclonal antibodies against the membrane receptor tyrosine kinases and their ligands are also available, particularly in the treatment of NSCLC, clear cell renal cell carcinoma, and breast cancer. In the AVOREN trial, treatment with interferon-alfa plus bevacizumab (anti-VEGF) increased median PFS in metastatic clear-cell from 5.5 to 10.2 months when compared with a placebo. Combination therapy with the VEGFR inhibitor ramucirumab, however, has shown only short increases in overall survival in gastric/gastroesophageal adenocarcinoma and NSCLC. ^, Combi­nation treatments with trastuzumab, a monoclonal antibody against HER-2, a subtype of EGFR, improve overall survival in HER-2-positive breast cancer in both localized, surgically resected, and metastatic disease.

Another use of monoclonal antibodies is in the treatment of hematologic malignancy through the targeted delivery of antimitotic agents. In CD33+ acute myeloid leukemia, combination therapy with gemtuzumab reduces relapse and overall 5-year survival. Combination therapy with brentuximab increases median PFS in CD30+ anaplastic large cell lymphoma and relapsed Hodgkin’s lymphoma.

Immunotherapies: Monoclonal Antibodies

The anti-CD20 monoclonal antibody rituximab, which induces B-cell death through antibody and complement-dependent cytotoxicity, has long been established as an adjunct to chemotherapy in diffuse large B-cell lymphoma and follicular lymphoma. More recently, the bispecific T-cell engager blinatumomab has been licensed for treatment in Philadelphia-chromosome negative B-cell precursor ALL (B-ALL). It consists of a CD3- and CD19-specific antibody fragment linked together, which binds and bridges the CD19+ tumor cell directly to CD8+ T cells via the CD3 domain, inducing direct cytotoxicity independent of MHC class I. ^, In a multicenter, randomized controlled trial studying relapsed/refractory B-ALL (n=405), blinatumomab compared to standard chemotherapy increased median overall survival (4 vs. 7.7 months) and had higher rates of complete remission (34% vs. 16%).

Immune Checkpoint Inhibitors

The efficacy of immune checkpoint inhibitors has been established throughout the phase III CheckMate and KEYNOTE trials, and they have largely superseded cytokine-based immunotherapy in renal cell carcinoma and melanoma.

In advanced treatment naive clear cell renal carcinoma, the CheckMate-214 trial (n=1096) showed higher response rate (42% vs. 27%) and overall survival favoring combination nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) versus sunitinib. KEYNOTE-426 (n=861) compared sunitinib with combination pembrolizumab (anti-PD-1) and axitinib (multitargeted small molecule tyrosine kinase) and reported improved overall and PFS. However, with a median follow-up period of 25.2 and 12.8 months, respectively, longer-term data from both trials are eagerly awaited. In metastatic melanoma, the CheckMate-066 trial (n=405) compared nivolumab with standard care chemotherapy and reported a dramatic improvement in median overall survival (37.5 vs. 11.2 months), outcomes which may be exceeded by combination therapy with ipilimumab, although with a significant increase in side effect profile. KEYNOTE-006 compared pembrolizumab (administered up to 2 years) with ipilimumab and has demonstrated superior median overall PFS after 5 years of follow up.

Checkpoint inhibitors are also established in the treatment of NSCLC. In KEYNOTE-407 (n=559) and KEYNOTE-189 (n=616) combination, pembrolizumab with platinum-based chemotherapy demonstrated superior median overall survival and PFS compared with chemotherapy alone in squamous and nonsquamous NSCLC, respectively, although better outcomes were seen in tumors with higher expression of PD-L1. ^, In CheckMate-227, nivolumab with ipilimumab also conferred longer median survival than standard chemotherapy, irrespective of PD-L1 expression.

Cellular Immunotherapy

Two CD-19-targeted CAR-T cell therapies have shown dramatic efficacy in the treatment of refractory or relapsed B-ALL and diffuse large B-cell lymphoma (DLBCL); however, the evidence base currently consists of small phase II studies which are in the early stages of follow up. In the multicenter phase II ELIANA trial, tisagenlecleucel was administered to 75 patients with B-ALL, leading to complete remission at 3 months in 81%, although in responders the relapse free survival fell to 59% at 12 months. In DLBCL, the ZUMA-1 and JULIET trials demonstrated complete response rates of 54% and 40% in patients treated with axicabtagene ciloleucel (n=101) and tisagenlecleucel (n=93), respectively. ^, CAR-T cells engineered to target myeloma and acute myeloid leukemia are under investigation, although trials in solid organ disease have yet to match the impressive response rates seen in hematologic disease.

Cardiovascular Sequelae of VEGF Inhibition

The direct or downstream signaling inhibition of the VEGF pathway through bevacizumab, ramucirumab, or tyrosine kinase inhibitors may be associated with hypertension, arterial and venous thromboembolism, left ventricular dysfunction, thrombotic microangiopathy, and dysrhythmias through QT prolongation. No specific treatment is indicated; initiation and withdrawal of the VEGF inhibitor in a patient with thromboembolic risk factors should be undertaken on an individual basis.

Immune-Related Adverse Events

Checkpoint inhibitors are associated with a group of multisystemic complications termed immune-related adverse events (irAEs), where inflammation and autoimmunity occur due to the loss of immunologic tolerance mediated through PD-1/PD-L1 and CTLA-4. The most commonly recognized irAEs include dermatologic, gastrointestinal, pulmonary, hepatic, and endocrine syndromes, which again may be graded using the CTCAE system.

The incidence of severe irAEs (CTCAE grade ≥3) is approximately 0.5%–13%, varying widely between trials, treatment, and disease types. Toxicity appears to be greater and dose-dependent with ipilimumab or combination anti-CTLA-4/PD-1/PD-L1 therapy, compared with anti-PD-1/PD-L1 therapy alone. ^, Dermatologic (rash, mucositis) and gastrointestinal (diarrhea, gastrointestinal bleeding, enterocolitis) irAEs are most commonly encountered. Critical care admission may be required for fluid balance monitoring, electrolyte disturbance, or specialist dressings, or following surgery for perforation.

In one case series, pneumonitis complicated 5%–10% of checkpoint inhibitor treatments, with a median onset of 2.8 months (range, 9 days to 19.2 months). In contrast to other irAEs, pneumonitis appears to be more common with anti-PD-1/PD-L1 treatment, and appearances on high-resolution computerized tomography (HRCT) scan are nonpathognomonic. Twenty-seven percent classified as CTCAE grade 3 or above, and within this group (n=12), there were five deaths. Importantly, in the minority of patients who progressed despite corticosteroids, little response was seen on the addition of second-line immunosuppressants, conferring high mortality, principally due to opportunistic infection.

In a recent meta-analysis, hypothyroidism was the most common endocrine irAE with an overall incidence of 6.6%, although the incidence of CTCAE grade 3 or above reactions was generally low (hypothyroidism, 0.12%; hypophysitis, 0.5%; primary adrenal insufficiency, 0.2%). However, given the variable onset and often vague symptoms associated with this group of irAEs, a high index of suspicion should be maintained and prompt critical care admission and specialist endocrine input sought for all critically unwell patients presenting with possible thyrotoxic or hypoadrenal symptoms.

The American Society of Clinical Oncology (ASCO) has provided consensus guidelines on the management of irAEs. Unfortunately, although there is ongoing research into markers of neutrophil activation such as CD177, there is no clinically available biomarker to identify checkpoint inhibitor toxicity, and therefore the general approach is a systematic multidisciplinary clinical assessment and investigations to exclude other etiologies, principally infection and de novo idiopathic autoimmune disease.

Established irAEs are treated by temporary cessation of the checkpoint inhibitor and corticosteroid therapy (0.5–1 mg/kg for grade 2, 1–2 mg/kg for grade 3 reactions) alongside prophylaxis against opportunistic infection until clinical response is observed. An alternative immunosuppressant, such as infliximab, azathioprine, or mycophenolate mofetil, may be used in refractory irAEs. Once symptoms have resolved, patients may be rechallenged with the checkpoint inhibitor, although treatment is usually permanently discontinued for patients encountering grade 4 reactions. Importantly, occurrence of an irAE, temporary treatment cessation, and immunosuppression does not appear to affect the efficacy of checkpoint inhibitor therapy.

Cytokine Release Syndrome

As the name suggests, this is constellation of symptoms resulting from massive cytokine release secondary to the antigen recognition and T-cell activation, and as such tends to be greater when there is a higher tumor burden. It most commonly complicates CAR-T-cell therapy—77% of patients in the ELIAN­A trial suffered cytokine release syndrome (CRS) —but it may also follow treatment with blinatumomab and monoclonal antibodies, such as rituximab and obinutuzumab. It is assoc­iated with high levels of interleukin (IL)-6, IL-10, IL-2, tumor necrosis factor (TNF), and interferon-alpha. It exhibits in a similar way to any major inflammatory response, with fever (often >40°C) as a minimum, tachycardia, hypotension, and hypoxemia, with potential for further progression to multiorgan failure. CRS timing is variable, but can be from a few hours postinfusion of CAR-T cells to more than a week.

Specific effects include:

• •
  

  Cardiovascular effects: tachycardia, refractory hypotension, arrhythmias, prolonged QT; echocardiogram findings may include reduced left ventricular ejection fraction

  
  
• •
  

  Respiratory: hypoxia, dyspnea, tachypnea secondary to pulmonary edema and/or pneumonitis

  
  
• •
  

  Renal: acute kidney injury

  
  
• •
  

  Gastrointestinal/hepatic: anorexia, nausea; colitis causing diarrhea; hyperbilirubinemia and transaminitis

  
  
• •
  

  Hematologic: anemia, thrombocytopenia, clotting abnormalities

While a number of grading systems have previously been used, CRS was incorporated in CTCAE v5, providing a simple and comparable classification ( Table 40.2 ).

Table 40.2

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