Tumor immunology and immunotherapy

Innate vs adaptive immunity

• Innate: fast, non-specific, no memory. Macrophages, NK cells, dendritic cells (DCs), neutrophils, complement. Uses pattern-recognition receptors (toll-like receptors, C-type lectin, NOD-like, RIG-I-like) that detect conserved molecular patterns: pathogen-associated (PAMPs, e.g., unmethylated CpG DNA) and damage-associated (DAMPs, e.g., HMGB1). Triggers cytokine production, cytotoxicity, nitric oxide, and complement activation.
• Adaptive: slower, specific, with memory. T cells (cellular) and B cells (humoral). T-cell (TCR) and B-cell (BCR) receptors are generated by random rearrangement of gene segments, creating an extremely diverse repertoire with effector and memory subsets. T-cell activation requires antigen presentation; B cells bind native antigen via BCR (T-independent responses need no presentation).
• Bridge: fragments from innate destruction are taken up by professional antigen-presenting cells (APCs) and presented to T-helper cells, which coordinate cytotoxic (CTL) and humoral (antibody) responses. Regulatory cells and cytokines maintain tolerance to self.

Antigen presentation

• MHC class I (HLA-A, HLA-B, HLA-C): all nucleated cells; presents endogenous (intracellular) peptides to CD8+ T cells.
• MHC class II (HLA-DR, HLA-DP, HLA-DQ): APCs (dendritic, macrophages, B cells); presents exogenous peptides to CD4+ T cells.
• MHC restriction: MHC polymorphisms determine which peptide epitopes bind and are presented, so a given T cell responds only to a specific peptide-MHC combination. This is why some peptide vaccines are HLA-type-specific.
• DCs are the most efficient APCs, functioning at the intersection of innate and adaptive immunity; they mature and migrate to lymph nodes to prime naive T cells.

Immune cell types

T-cell biology & activation

• T-cell signaling complex: TCR dimer + accessory molecule (CD4 or CD8) + CD3 signal-transduction module. Conventional alphabeta T cells recognize peptide-MHC, not intact protein (exceptions: NKT see CD1d-lipid, MAIT see MR1, many gammadelta unrestricted).
• Three signals for activation: (1) TCR-peptide-MHC, (2) CD28 co-stimulation via CD80/CD86 (B7) on the APC, (3) cytokines. Failure of co-stimulation causes anergy.
• CD28 family: stimulatory CD28 (high expression, low affinity) vs inhibitory CTLA-4 (low expression, high affinity), both binding B7 (CD80/CD86).
• Co-stimulatory receptors: CD28, 4-1BB (CD137), CD27, OX40 (CD134), ICOS (CD278), GITR (CD40L/CD154 is a T-cell ligand for CD40 on B cells/APCs, not a T-cell costimulatory receptor).
• Co-inhibitory receptors (immune checkpoints): CTLA-4 (CD152), PD-1 (CD279), BTLA (CD272), LAG-3 (CD223), TIM-3 (CD366), VISTA, TIGIT, CD160, CD244.

The cancer-immunity cycle

• An iterative sequence (Chen & Mellman) describing how antitumor immunity is generated and amplified:
  1. Release of tumor antigens (cell death from tumor turnover, chemotherapy, or radiotherapy).
  2. Antigen capture and processing by DCs.
  3. Priming and activation of T cells in the lymph node (co-stimulation, the CTLA-4 checkpoint operates here).
  4. Trafficking of T cells to the tumor.
  5. Infiltration into the tumor bed.
  6. Recognition of tumor cells by T cells (peptide-MHC).
  7. Killing of tumor cells, releasing more antigen and re-starting the cycle (the PD-1/PD-L1 checkpoint operates here, in the effector phase).
• Each step can be a bottleneck exploited by tumors; therapies aim to restore flow through the cycle.

Immune surveillance & immunoediting

• The immune system continually recognizes and removes malignant cells. Evidence: increased cancer risk in immunosuppressed patients, spontaneous regressions, response to immunosuppression withdrawal, and prognostic value of CD8+ infiltration (melanoma, ovarian).
• Three phases of immunoediting: elimination (immune destruction of nascent tumor), equilibrium (residual tumor held dormant), and escape (tumor grows by avoiding immune recognition/destruction).
• Effective surveillance needs tumor antigens (neoantigens from mutations, cancer-testis antigens, differentiation/lineage antigens, overexpressed self-proteins) presented on MHC. High mutational burden (e.g., MMR deficiency) generates more neoantigens and predicts checkpoint-inhibitor response.

Immune escape mechanisms

• Downregulation of MHC class I and antigen-presentation machinery.
• Expression of inhibitory ligands: PD-L1/PD-L2 (engage PD-1); a key role of PD-1+ T cells is to secrete IFN, which upregulates tumor PD-L1 (a targetable dependency).
• FAS ligand expression by tumor ("FAS counterattack" killing effector T/NK cells); antiapoptotic molecules.
• Suppressive milieu: Treg and MDSC infiltration; TGF-β, IL-10, prostaglandin E2; Th2 skewing; TCR CD3 zeta-chain downregulation.

Checkpoint biology

• CTLA-4 (priming phase, lymph node): low-abundance, high-affinity receptor induced on activated naive T cells; outcompetes CD28 for B7. Blockade (ipilimumab, tremelimumab) augments T-cell priming; efficacy also linked to ADCC-mediated Treg depletion.
• PD-1 / PD-L1 (effector phase, tumor microenvironment): mediates peripheral tolerance and T-cell exhaustion; PD-L1 is expressed by tumors. Blockade (pembrolizumab, nivolumab, cemiplimab, dostarlimab, atezolizumab, durvalumab, avelumab, retifanlimab) reinvigorates effector T cells. These mechanisms are non-redundant, which is why dual blockade adds efficacy (and toxicity).
• LAG-3: relatlimab (with nivolumab in melanoma).
• TIM-3, TIGIT: investigational (see 2024-2026 updates).
• Treg cells (CD4+CD25+FoxP3+): suppress immune response.

Cancer immunotherapy

• Mechanism: release brakes on T-cells.
• Antibody engineering: therapeutic mAbs are chimeric (-ximab, ~65 to 70% human), humanized (-zumab, ~95% human), or fully human (-umab). IgG1 is the strongest effector isotype: ADCC via Fcgamma receptors (e.g., NK CD16) and CDC via C1q/classical complement (not cellular Fc receptors); IgG4 is used when only signaling blockade is desired (most PD-1 antibodies are IgG4).
• Predictive biomarkers:
  • PD-L1 expression (TPS, CPS).
  • Tumor mutational burden (TMB), pembrolizumab tumor-agnostic for TMB ≥10 mut/Mb.
  • MSI-H / dMMR: pembrolizumab tumor-agnostic (MSI-H or dMMR); dostarlimab tumor-agnostic (dMMR-specified).
  • Tumor-infiltrating lymphocytes (TILs).
  • Immune-related AEs (irAE): dermatitis, colitis, pneumonitis, hepatitis, endocrinopathies, myocarditis, neurologic.
  • Hyperprogression (rare): ↑↑ tumor growth on IO.
  • Pseudoprogression (rare): apparent radiographic ↑ followed by response.
• irAE management: withhold for moderate irAE or symptomatic endocrinopathy; systemic corticosteroids for symptomatic/severe events; add infliximab, tocilizumab, vedolizumab, or mycophenolate for steroid-refractory cases. CTLA-4 agents (and dual blockade) cause more and higher-grade toxicity than single-agent PD-1/PD-L1. Steroids given for irAE do not appear to impair antitumor response, but steroids before starting ICI are discouraged. Most irAEs occur in the first 4 to 6 months but can be late or permanent (endocrine).

• Mechanisms: complement-mediated cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC via NK/macrophage Fc receptors), direct apoptosis, and blockade of receptor-ligand signaling.
• Anti-CD20: rituximab (chimeric IgG1; NHL, CLL; screen for hepatitis B, risk of PML), ofatumumab (binds membrane-proximal epitope, strong CDC), obinutuzumab (glycoengineered type 2, enhanced ADCC/direct death, less CDC).
• Anti-CD52: alemtuzumab (CLL; profound lymphopenia, opportunistic infections). Anti-HER2: trastuzumab, pertuzumab. Anti-EGFR: cetuximab, panitumumab. Anti-VEGF/VEGFR: bevacizumab, ramucirumab. Anti-CD38: daratumumab. Anti-CCR4: mogamulizumab.

• CAR-T cells: autologous T cells engineered with a chimeric antigen receptor (extracellular antibody-derived recognition domain + transmembrane domain + intracellular CD3ζ signaling + costimulation, e.g., CD28 or 4-1BB). CARs recognize surface antigen without MHC restriction (antigen is not processed/presented), unlike TCR-T.
• CD19 CAR-T: tisagenlecleucel (kymriah), axicabtagene (yescarta), brexucabtagene (tecartus), lisocabtagene (breyanzi), obecabtagene (aucatzyl, adult B-ALL, 2024). For B-cell ALL, NHL, MCL.
• BCMA CAR-T: idecabtagene (abecma), ciltacabtagene (carvykti). For MM.
• TCR-T: engineered T-cell receptor; HLA-restricted (depends on processing and presentation of a single epitope). Active in some solid tumors (afami-cel/Tecelra for eligible HLA-A*02:01P/02:02P/02:03P/02:06P (contraindicated in HLA-A*02:05P) + MAGE-A4+ unresectable/metastatic synovial sarcoma after chemo, adults, FDA accelerated approval Aug 2024) and heme malignancies.
• TIL therapy: lifileucel (Amtagvi) for melanoma, FDA Feb 2024; supported by high-dose IL-2.
• Resistance: loss of the target antigen, loss of T-cell persistence/activity over time.
• Toxicities: CRS (systemic inflammatory response from cytokine release, IL-1/IL-2/IL-6; manage with tocilizumab (first-line anti-IL-6R) plus corticosteroids by grade; siltuximab is an off-label option for refractory cases), ICANS/CRES (confusion, aphasia, seizures, cerebral edema; steroids), B-cell aplasia, prolonged cytopenia, hypogammaglobulinemia, secondary T-cell malignancy (class warning 2024).

• Mechanism: a fusion of two single-chain variable fragments (scFvs), one binding T-cell CD3 and the other a tumor antigen, physically bridging the T cell to the tumor cell to trigger activation, granule release, and serial killing. scFvs lack an Fc domain, so they do not mediate CDC or ADCC. Blinatumomab (CD19xCD3) has a 2-hour half-life and is given as a continuous 4-week IV infusion.
• Approved: blinatumomab (CD19, B-ALL, including MRD+), tarlatamab (DLL3, SCLC), tebentafusp = ImmTAC (soluble affinity-enhanced TCR fused to anti-CD3 scFv), targets gp100 peptide on HLA-A*02:01, uveal melanoma (not a two-scFv BiTE). For MM: teclistamab (BCMA), elranatamab (BCMA), linvoseltamab (BCMA, 2025), talquetamab (GPRC5D). For B-cell lymphoma (CD20xCD3): mosunetuzumab (FL), epcoritamab (DLBCL, FL), glofitamab (DLBCL).
• Class toxicities: CRS (premedicate, step-up dosing, inpatient monitoring for first doses), ICANS, infections. Blinatumomab neurologic events usually resolve after interruption/discontinuation, but can be severe, life-threatening, or fatal (boxed warning); may require steroids or permanent discontinuation.

• Sipuleucel-T (Provenge): autologous cellular vaccine for asymptomatic/minimally symptomatic mCRPC; peripheral mononuclear cells cultured with a PAP-GM-CSF fusion protein (PA2024) to present prostatic acid phosphatase, then reinfused. Modest OS benefit.
• Talimogene laherparepvec (T-VEC): intralesional oncolytic HSV-1 (deletions of ICP34.5 and ICP47, insertion of GM-CSF) for melanoma; dual action of direct lysis plus in-situ vaccination.
• Personalized neoantigen vaccines (mRNA): Moderna mRNA-4157 + pembrolizumab in melanoma.

• IL-2 (high-dose, aldesleukin): melanoma, RCC. T-cell/NK growth factor; ~15 to 20% objective response, ~6 to 7% complete (often durable). Capillary leak syndrome resembling septic shock, ICU-level care.
• IFN-α: hairy cell leukemia, melanoma adjuvant (less used now). Type I IFN enhances MHC I; IFN-γ also induces MHC II and activates macrophages.
• Recombinant IL-15 (investigational; approved post-lifileucel support is high-dose IL-2/aldesleukin). The IL-15 superagonist complex nogapendekin alfa inbakicept (N-803, Anktiva) is FDA approved (Apr 2024) with intravesical BCG for BCG-unresponsive NMIBC with CIS.

Hematologic + transplant immunology

• HLA matching for allogeneic HSCT.
• GVHD: donor T-cells attacking recipient. Acute (skin, GI, liver) vs chronic (skin, eyes, mouth, lungs, scleroderma-like).
• GVL effect (graft-vs-leukemia): therapeutic in allo-HSCT; donor-derived antileukemic effect that overlaps with GVHD but can occur without clinical GVHD (also NK- and leukemia-antigen-mediated). Higher relapse with T-cell-depleted or autologous grafts.
• Donor lymphocyte infusion (DLI): adoptive therapy for relapse after allo-HSCT; durable molecular remissions in CML (modest in AML, rare in ALL); can clear EBV-associated PTLD. Main risk is GVHD.
• CMV reactivation post-allo HSCT, letermovir prophylaxis.

2024-2026 immunotherapy landscape updates

• TIGIT status: tiragolumab + atezo NEGATIVE in 1L NSCLC (SKYSCRAPER-01) and 1L ES-SCLC (SKYSCRAPER-02); NEGATIVE in 1L nonsquamous NSCLC with chemo (SKYSCRAPER-06); signal only in 1L HCC (phase 1b/2 MORPHEUS-Liver, ORR 43% vs 11% with atezo/bev; phase 3 IMbrave152/SKYSCRAPER-14 subsequently stopped tiragolumab per sponsor recommendation). Vibostolimab + pembro (KEYVIBE): program discontinued for futility (Merck, Dec 2024; KEYVIBE-003/006/007), KEYVIBE-010 also stopped. TIGIT class efficacy remains uncertain outside select settings.
• PD-1xVEGF bispecifics: ivonescimab (Summit), HARMONi-2 (Xiong Lancet 2025) beat pembrolizumab head-to-head in 1L PD-L1+ NSCLC in China (mPFS 11.1 vs 5.8 mo, HR 0.51). HARMONi-6 (China, 1L squamous NSCLC, ivonescimab + chemo vs tislelizumab + chemo) positive (PFS HR 0.60); global phase 3 HARMONi-3 ongoing. First head-to-head anti-PD-1 win.
• Personalized mRNA neoantigen vaccines: V940 (mRNA-4157) + pembrolizumab, KEYNOTE-942 (Weber Lancet 2024) in resected stage IIIB-IV melanoma: 44% RFS reduction vs pembro alone (HR 0.56). Phase 3 INTerpath-001 ongoing. Autogene cevumeran (BioNTech) in resected PDAC (Rojas Nature 2023, phase 1): personalized neoantigen mRNA vaccine with atezolizumab then mFOLFIRINOX (not MRD-guided).
• T-cell engager toxicity generic: CRS clusters at first 1 to 2 doses (step-up), premedicate dex/APAP/H1; ICANS lower vs CAR-T; profound and prolonged hypogammaglobulinemia esp. BCMA bispecifics, use IVIG. Higher infection-related mortality than CAR-T in real-world MM cohorts.
• Novel TIL products: OBX-115 (IL-2-independent membrane-bound IL-15 TIL); TIL + IO combinations (IOV-COM-202).
• Allogeneic "off-the-shelf" CAR-T: ALLO-501A (cema-cel; CD19, TALEN-edited TRAC/CD52), CB-010 (CD19, CRISPR-edited), emerging, faster access but rejection/persistence limits.
• Second malignancy after CAR-T (T-cell): FDA class boxed warning Apr 2024, post-marketing T-cell lymphomas (some CAR-transgene+); lifetime hematologic monitoring.

High-yield immunology pearls

• CTLA-4 (priming, lymph node) vs PD-1 (effector phase, tumor).
• MHC I to CD8; MHC II to CD4; T cells see peptide-MHC only (MHC restriction).
• NK cells kill MHC-I-low cells and mediate ADCC.
• MSI-H, TMB-high, PD-L1 = IO predictive biomarkers.
• CRS = tocilizumab + steroids; ICANS = steroids.
• CAR-T is MHC-independent (surface antigen); TCR-T is HLA-restricted.
• CAR-T: CD19 (B-ALL, NHL); BCMA (MM).
• BiTE: bridges CD3 (T cell) to tumor antigen. Classic BiTE (blinatumomab) is scFv-scFv, no Fc, no CDC/ADCC; tarlatamab (HLE BiTE) and IgG-based bispecifics (teclistamab, etc.) retain an Fc (effector-silenced).
• Tarlatamab = DLL3 BiTE for SCLC; Tebentafusp = HLA-A*02:01 + gp100 for uveal melanoma.
• Lifileucel = TIL for melanoma; Sipuleucel-T = DC vaccine for mCRPC.
• Allo-HSCT GVL effect is therapeutic; DLI treats relapse (best in CML).
• IL-2 capillary leak.