Oncologic Monoclonal Antibodies, Checkpoint Inhibitors & CAR-T

How monoclonal antibodies work

Mechanisms. Antibodies bind extracellular or soluble targets and act by antibody-dependent cellular cytotoxicity (NK cells engage the Fc portion through FcγRIII), complement-dependent cytotoxicity, receptor or ligand blockade, or delivery of a toxic payload. Unlike small-molecule inhibitors, they are given parenterally and cannot reach intracellular targets (antibody-drug conjugates are internalized only to release their payload).

Names. Chimeric antibodies (-ximab: rituximab, cetuximab) keep whole mouse variable regions and are the most immunogenic; humanized antibodies (-zumab: trastuzumab, bevacizumab) keep only the mouse antigen-binding loops (CDRs); fully human antibodies end in -umab (panitumumab, daratumumab).

Naked antibodies: targets and toxicities

Rituximab. This chimeric anti-CD20 antibody depletes B cells through ADCC, complement, and apoptosis; it also treats ITP, rheumatoid arthritis, ANCA vasculitis, and pemphigus vulgaris. First infusions often cause cytokine-release reactions. Hepatitis B can reactivate fatally, so HBsAg and anti-HBc are checked first and carriers receive antiviral prophylaxis. Progressive multifocal leukoencephalopathy (JC virus infection of oligodendrocytes, with multifocal nonenhancing white matter lesions rather than the ring-enhancing lesions of toxoplasmosis) and hypogammaglobulinemia with infections are further risks.

Trastuzumab and pertuzumab. Trastuzumab binds HER2 domain IV; pertuzumab binds domain II and blocks dimerization. Because HER2 supports cardiomyocyte survival signaling, blockade lowers LVEF without killing myocytes; the dysfunction is not dose-related and usually recovers when the drug is held. Anthracycline injury, by contrast, is myocyte necrosis from free radicals and topoisomerase IIβ, cumulative dose-dependent, and irreversible (dilated cardiomyopathy). LVEF is checked at baseline and about every 3 months.

Bevacizumab. Binding VEGF-A blocks angiogenesis in colorectal, nonsquamous lung, renal, ovarian, and cervical cancers and glioblastoma. Toxicities mirror VEGF's physiologic roles: hypertension, proteinuria, bleeding, GI perforation, impaired wound healing (held around surgery), and arterial thromboembolism. It is avoided in squamous NSCLC because of fatal hemoptysis.

Cetuximab and panitumumab. Cetuximab (chimeric) and panitumumab (human) block EGFR. In metastatic colorectal cancer they help only when KRAS and NRAS are wild type, because mutant RAS signals downstream regardless, so extended RAS testing is mandatory. Cetuximab with radiation treats head and neck SCC. Toxicities: acneiform rash, hypomagnesemia from renal magnesium wasting, and infusion reactions; severe first-dose cetuximab anaphylaxis occurs with preexisting IgE against alpha-gal (galactose-α-1,3-galactose) after tick bites.

Daratumumab and alemtuzumab. Daratumumab kills CD38-rich myeloma plasma cells by ADCC, complement, and phagocytosis and causes frequent infusion reactions. Reagent red cells also carry CD38, so antibody screens become panreactive: type and screen before the first dose, and labs treat cells with DTT. Alemtuzumab targets CD52 on T and B lymphocytes and monocytes, causing infusion reactions and profound, prolonged lymphopenia with CMV reactivation and Pneumocystis risk, so prophylaxis and monitoring are needed; in multiple sclerosis its immune reconstitution triggers thyroid disease, ITP, and anti-GBM disease.

Antibody-drug conjugates and bispecific engagers

Conjugates. A linker attaches a cytotoxic payload that is released after internalization. Brentuximab vedotin delivers MMAE (monomethyl auristatin E, a microtubule inhibitor) to CD30+ cells in Hodgkin lymphoma, ALCL, and CD30+ PTCL, causing peripheral neuropathy, neutropenia, and rarely PML. Trastuzumab deruxtecan delivers a topoisomerase I inhibitor to HER2-expressing cells; its membrane-permeable payload also kills neighbors (bystander effect), so it works even in HER2-low breast cancer. Its boxed toxicity is interstitial lung disease: new cough, dyspnea, or ground-glass opacities mean holding the drug and giving corticosteroids, with permanent discontinuation if moderate or worse. Gemtuzumab ozogamicin (CD33, AML) and inotuzumab ozogamicin (CD22, B-ALL) carry calicheamicin payloads that can cause hepatic sinusoidal obstruction syndrome.

Bispecific T-cell engagers. Blinatumomab links CD19 on B-ALL blasts to CD3 on T cells, forming a cytolytic synapse without MHC restriction. Its very short half-life requires continuous infusion for relapsed or MRD-positive B-ALL, and it can cause cytokine release syndrome and neurotoxicity.

Immune checkpoint inhibitors

Mechanism. CTLA-4 outcompetes the costimulatory receptor CD28 for B7 (CD80/86) on antigen-presenting cells, restraining priming in lymph nodes; ipilimumab blocks it. PD-1 on activated T cells binds PD-L1 on tumor cells, exhausting effector T cells in tissues; pembrolizumab and nivolumab block PD-1, and atezolizumab and durvalumab block PD-L1. Immunogenic tumors respond best, such as melanoma, lung and renal cancers, and mismatch repair-deficient (MSI-high) tumors.

Immune-related adverse events. Loss of tolerance can inflame any organ: dermatitis, colitis, hepatitis, pneumonitis, thyroiditis (often transient hyperthyroidism, then hypothyroidism), hypophysitis (headache, low ACTH and TSH), adrenalitis, type 1 diabetes presenting as DKA, nephritis, and rare but often fatal myocarditis. Combined CTLA-4 plus PD-1 blockade produces the most irAEs.

CAR-T cell therapy

Construction. Leukapheresed T cells are transduced by a viral vector with a chimeric antigen receptor (antibody-derived scFv, a CD28 or 4-1BB costimulatory domain, and CD3ζ), expanded, and reinfused after fludarabine/cyclophosphamide lymphodepletion. Recognition is MHC-independent, so tumors escape instead by losing the antigen (CD19-negative relapse). CD19 CAR-T treats relapsed B-ALL and B-cell lymphomas and causes on-target B-cell aplasia with hypogammaglobulinemia (IVIG replacement); BCMA CAR-T treats multiple myeloma. Other risks include prolonged cytopenias, infections, and rare secondary T-cell malignancies.

Tocilizumab penetrates the CNS poorly, so ICANS is treated with corticosteroids; the IL-1 receptor antagonist anakinra is sometimes added for refractory cases.