Immunotherapy and Cancer Immunology

Introduction to Cancer Immunology

The immune system continuously surveys for and eliminates nascent neoplasms through a process termed cancer immunoediting—comprising elimination, equilibrium, and escape phases. In the elimination phase, innate and adaptive immune cells recognise and destroy early cancer cells. In equilibrium, immune pressure shapes tumour evolution selecting for less immunogenic variants. In escape, tumours acquire characteristics that evade immune destruction—a pre-condition for clinically apparent cancer. The immunoediting concept explains why cancers detected clinically have already evolved immune escape mechanisms, and why immunotherapy must overcome these established evasion strategies.

The immune system recognises tumours through tumour-associated antigens (TAAs—overexpressed self proteins), cancer-testis antigens (normally restricted to germ cells, aberrantly expressed in cancer), and neoantigens (novel peptides from cancer-specific non-synonymous mutations displayed on MHC class I). Neoantigens are the most immunogenic because they are not subject to central tolerance; tumour mutational burden (TMB)—the count of somatic mutations per megabase—predicts neoantigen load and therefore immunotherapy responsiveness. Microsatellite instability-high (MSI-H) and mismatch repair deficient (dMMR) tumours with highest TMB show best response to anti-PD-1 therapy across tumour histologies.

Checkpoint Inhibitors

CTLA-4 Pathway

CTLA-4 (Cytotoxic T-Lymphocyte-Associated protein 4) is upregulated on activated T cells and competes with CD28 for binding CD80/CD86 on APCs, delivering an inhibitory signal dampening T cell activation. Ipilimumab, an anti-CTLA-4 IgG1 monoclonal antibody, blocks CTLA-4, releasing the brake on T cell activation—expanding effector T cell populations and depleting Tregs in tumours. James Allison's work establishing CTLA-4 as a promising cancer target and ipilimumab's clinical efficacy in melanoma (first immunotherapy survival benefit in metastatic melanoma) earned him the 2018 Nobel Prize in Physiology or Medicine (shared with Tasuku Honjo for PD-1). Ipilimumab is approved in melanoma, RCC, NSCLC, and other tumours in combination with nivolumab.

PD-1/PD-L1 Pathway

PD-1 is expressed on exhausted T cells in tumours. Its ligands PD-L1 and PD-L2 are upregulated on tumour cells and tumour-associated macrophages in response to interferon-gamma in the immune-active microenvironment. PD-L1-PD-1 engagement delivers inhibitory signals maintaining T cell exhaustion. Anti-PD-1 (nivolumab, pembrolizumab) and anti-PD-L1 (atezolizumab, durvalumab) antibodies block this interaction, reinvigorating exhausted T cells. Pembrolizumab has received FDA approval for 15+ tumour types including the first histology-agnostic approvals—MSI-H/dMMR solid tumours and TMB-high solid tumours—based purely on molecular features independent of tissue of origin, a paradigm shift in oncological classification.

Cellular Immunotherapy

CAR-T Cell Therapy

Chimeric antigen receptor (CAR) T cells combine antibody-based antigen recognition with T cell signalling in a single synthetic receptor. Second-generation CARs contain scFv antigen-binding domain, transmembrane domain, CD3-zeta signalling domain, and CD28 or 4-1BB co-stimulatory domain. Patient T cells are leukapheresed, transduced with the CAR, expanded to billions, and reinfused after lymphodepletion. CD19-targeted CARs (tisagenlecleucel, axicabtagene) achieve 70-85% complete remission in relapsed/refractory B-ALL—patients who had failed all prior therapies. BCMA-targeted CARs in multiple myeloma achieve high response rates after progression through antibody drug conjugates. Challenges include manufacturing (3-4 weeks per patient), CRS toxicity management, and solid tumour applications.

NK Cell Therapies

Natural killer (NK) cells recognise and kill targets lacking MHC class I through 'missing self' recognition, complementing T cell killing. NK cells can be allogeneic—not causing GvHD because they lack T cell receptor—enabling off-the-shelf therapy from healthy donors. CAR-NK cells are engineered with the same antigen recognition approach as CAR-T but with NK cell signalling domains. Phase I/II trials of CD19-targeted CAR-NK cells in B cell malignancies showed responses without CRS or neurotoxicity. Cord blood-derived and iPSC-derived NK cells provide scalable allogeneic manufacturing. NK cells may be better suited than CAR-T cells for solid tumour applications due to their ability to traffic to tumours and kill through multiple redundant mechanisms.

Cancer Vaccines

Personalised neoantigen vaccines—mRNA or peptide vaccines encapsulating each patient's specific tumour neoantigens (predicted by tumour genome sequencing and computational HLA binding prediction)—are in clinical development. Moderna and BioNTech use mRNA platforms; early data in melanoma combined with anti-PD-1 showed significant improvement in recurrence-free survival. The first personalised cancer vaccine showing survival benefit in a randomised trial (mRNA-4157 in high-risk stage II-III melanoma adjuvant setting) reported 44% reduction in recurrence or death with combination pembrolizumab therapy versus pembrolizumab alone in 2023. Shared antigen vaccines targeting tumourspecific antigens expressed in most patients of a given cancer type (PSA DNA vaccine in prostate cancer, WT1 peptide vaccine in AML) represent a complementary scalable approach.

Examples and Applications

Example 1: Ipilimumab in Melanoma

The first Phase III trial of ipilimumab in previously treated metastatic melanoma (MDX010-20, 2010) showed improved overall survival (10.1 months vs. 6.4 months) against an active control—the first drug ever showing survival benefit in metastatic melanoma. Long-term follow-up established a plateau in the survival curve—approximately 20% of patients surviving 10+ years, essentially cured. Responders were concentrated among patients with specific T cell infiltration patterns and baseline immune parameters. Ipilimumab+nivolumab combination improved 5-year survival to 52% in advanced melanoma, illustrating the power of combination checkpoint blockade and the durable benefit of immunological responses.

Example 2: MSI-H Pan-Cancer Immunotherapy

Microsatellite instability-high (MSI-H) cancers—from mismatch repair deficiency generating thousands of frameshifts and neoantigens—respond exceptionally well to anti-PD-1 across all histologies. Pembrolizumab received the FDA's first histology-agnostic approval (2017) for MSI-H/dMMR solid tumours regardless of where they originate, based on overall response rates of 40-55% across 12 solid tumour types. This approval fundamentally shifted oncological paradigm from treating 'organ of origin' to treating molecular 'tumour biology'—the same drug approved for the same molecular feature in colon, endometrial, gastric, brain, and any other MSI-H cancer. Genetic testing for MSI-H status is now standard across solid tumour workup.

Example 3: Bispecific Antibodies

Bispecific antibodies engage two different antigens simultaneously—typically a tumour cell antigen and CD3 on T cells, physically recruiting T cells to tumours without prior sensitisation. Blinatumomab (CD19xCD3 bispecific) achieves remission in relapsed/refractory B-ALL at doses eliminating tumours with very low amounts of drug through T cell engagement. Teclistamab (BCMAxCD3) and other BCMA bispecifics achieve high responses in relapsed/refractory myeloma. Tebentafusp (gp100xCD3) bispecific for uveal melanoma is the first solid tumour bispecific approval. More than 20 bispecific antibodies are in late clinical development for solid and haematological malignancies. Trispecific formats and bispecific ADCs further extend this platform.

Example 4: Tumour-Infiltrating Lymphocyte Therapy

TIL therapy—adoptive transfer of patient's own expanded tumour-infiltrating T cells—exploits the pre-existing antitumour T cell repertoire in tumours. Melanoma TIL therapy in refractory patients achieved ~30-40% response including durable complete responses in patients who failed all prior therapies including checkpoint inhibitors. Iovance Biotherapeutics' lifileucel received FDA approval for unresectable or metastatic melanoma in 2024—the first TIL therapy approved. Manufacturing involves tumour resection, TIL culture over 6 weeks, lymphodepletion, and reinfusion —logistically complex but producing autologous cells with endogenous tumour recognition. Solid tumour-specific TIL therapy is being developed for NSCLC, cervical, and head/neck cancers.

Example 5: Combination Immunotherapy and Chemotherapy

Combining immunotherapy with chemotherapy (rather than replacing chemotherapy) has become standard across lung, bladder, triple-negative breast, and other cancers. Pembrolizumab + platinum-based chemotherapy in NSCLC improved overall survival versus chemotherapy alone in KEYNOTE-189/407, establishing a new first-line standard. Chemotherapy's immune-modulatory effects contributing to benefit include: immunogenic cell death releasing DAMPs (damage-associated molecular patterns) promoting dendritic cell maturation, tumour antigen release for T cell priming, reduction of immunosuppressive MDSCs, and improved T cell trafficking to tumours. Understanding immunogenic cell death mechanisms guides which chemotherapy agents combine best with checkpoint inhibitors.

Example 6: ADCP and Macrophage-Based Immunotherapy

Antibody-dependent cellular phagocytosis (ADCP) by macrophages contributes to responses from therapeutic monoclonal antibodies. CD47 is overexpressed on cancer cells—signalling 'don't eat me' to macrophages through SIRPalpha. Anti-CD47 antibodies (magrolimab) block this signal, enabling macrophage recognition even as an opsonising antibody improves ADCP. Magrolimab + azacitidine combination in AML and MDS showed high response rates in Phase I and Phase II trials in patients with TP53 mutations—a subset with worst outcomes from standard therapy. Macrophages can also be CAR-engineered (CAR-macrophages) for phagocytosis of antigen-expressing targets, representing a distinct cellular immunotherapy arm.

Example 7: Oncolytic Viruses

Oncolytic viruses preferentially infect and replicate in cancer cells (exploiting tumour-specific defects in antiviral responses reducing IFN pathway activity), causing direct tumour cell lysis and releasing tumour antigens and DAMPs that stimulate systemic antitumour immunity—an in situ cancer vaccine effect. T-VEC (talimogene laherparepvec)—an attenuated HSV-1 encoding GM-CSF—is approved for unresectable melanoma, showing durable complete responses in injected and distant tumours (abscopal effect). Combination of T-VEC with anti-PD-1 pembrolizumab is in Phase III trials for melanoma and other tumours. Engineered oncolytic viruses expressing checkpoint inhibitors, tumour antigens, and bispecifics are next-generation approaches.

Example 8: Adoptive Transfer and Solid Tumours

Achieving CAR-T efficacy in solid tumours is challenging compared to haematological malignancies due to lack of universal solid tumour antigens, hostile immunosuppressive tumour microenvironment, poor T cell trafficking and infiltration, and T cell exhaustion in the tumour. Strategies being developed: armoured CAR-T cells secreting IL-15 or IL-21 for autocrine support; TGF-beta-resistant CARs enabling function in TGF-beta-rich tumours; co-expression of dominant-negative TGF-beta receptor; combined PD-1 KO; targeting tumour stroma antigens (FAP, VEGFR2) alongside tumour cells; and regional delivery (intratumoral or intrathecal injection for brain tumours). GD2-targeted CAR-T cells in DIPG showed promising early activity supporting continued development in this previously treatment-resistant paediatric brain tumour.

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