Immunotherapy and Cancer: How the Immune System Fights Tumors

How Tumors Evade the Immune System

The immune system detects and eliminates most abnormal cells before they become clinically apparent cancers, a process called immune surveillance. CD8+ cytotoxic T cells recognize mutant proteins (neoantigens) displayed on tumor cell surfaces by MHC class I molecules and kill the cells. NK cells detect and destroy tumor cells that have downregulated MHC class I expression. Macrophages and dendritic cells phagocytose tumor debris and present tumor antigens to activate adaptive immune responses. The cancers that do develop and become clinically detectable are those that have successfully evolved strategies to evade this surveillance.

Tumors escape immune destruction through multiple complementary mechanisms. Many tumors downregulate MHC class I expression, reducing the visibility of neoantigens to T cells. Tumors often upregulate immune checkpoint ligands, particularly PD-L1 (programmed death-ligand 1), which binds to PD-1 on T cells and sends an inhibitory signal that shuts down T cell cytotoxicity. The tumor microenvironment is frequently immunosuppressive, populated by regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) that produce cytokines like TGF-beta, IL-10, and VEGF, all of which dampen anti-tumor immune responses.

Tumors also exploit metabolic constraints. Rapidly growing tumors consume glucose and amino acids from the local environment, starving T cells of the nutrients they need for activation and proliferation. The acidic, hypoxic conditions inside solid tumors further impair T cell function. Some tumors produce the enzyme indoleamine 2,3-dioxygenase (IDO), which depletes the amino acid tryptophan and generates immunosuppressive metabolites that inhibit T cell proliferation and promote Treg differentiation. Understanding these evasion mechanisms has been essential for designing immunotherapies that counteract them.

Checkpoint Inhibitors

Immune checkpoints are inhibitory receptors on T cells that normally prevent excessive immune activation and autoimmunity. Cancer cells hijack these natural brakes to shut down anti-tumor T cell responses. Checkpoint inhibitor drugs are monoclonal antibodies that block these inhibitory receptors, releasing the brakes and allowing T cells to attack tumors.

The first checkpoint inhibitor approved by the FDA was ipilimumab (Yervoy) in 2011, which blocks CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). CTLA-4 competes with the co-stimulatory receptor CD28 for binding to B7 ligands on antigen-presenting cells. When CTLA-4 wins this competition, T cell activation is suppressed. By blocking CTLA-4, ipilimumab tips the balance toward CD28-mediated co-stimulation and T cell activation. The pivotal trial in metastatic melanoma showed that ipilimumab improved median overall survival from 6.4 months to 10.1 months, and approximately 20 percent of treated patients achieved durable long-term survival exceeding 10 years, a dramatic result in a cancer that previously had a median survival of 6 to 9 months with chemotherapy.

Anti-PD-1 and anti-PD-L1 antibodies have proven even more effective and broadly applicable. Pembrolizumab (Keytruda) and nivolumab (Opdivo) block PD-1 on T cells, while atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio) block PD-L1 on tumor cells. By disrupting the PD-1/PD-L1 interaction, these drugs prevent tumors from transmitting the "stand down" signal to T cells. Anti-PD-1 therapy is now approved for more than 20 different cancer types, including melanoma, non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, bladder cancer, head and neck squamous cell carcinoma, and microsatellite instability-high (MSI-H) cancers regardless of tissue origin. This last approval, based on a shared molecular feature rather than anatomical location, was the first tissue-agnostic cancer drug approval in FDA history.

Response rates to single-agent PD-1 blockade range from 15 to 20 percent in unselected patient populations to 40 to 60 percent in cancers with high PD-L1 expression or high tumor mutational burden (TMB). Tumors with more mutations produce more neoantigens, giving the immune system more targets to recognize. Combining anti-CTLA-4 with anti-PD-1 (the ipilimumab-nivolumab combination) increases response rates further, to approximately 58 percent in melanoma, but also significantly increases the rate of immune-related adverse events.

CAR-T Cell Therapy

Chimeric antigen receptor (CAR) T cell therapy takes a fundamentally different approach: rather than removing inhibitory brakes from existing T cells, it engineers the patient's own T cells to express a synthetic receptor that targets a specific protein on the surface of cancer cells. The CAR combines an extracellular antibody-derived binding domain (typically a single-chain variable fragment, or scFv) with intracellular T cell signaling domains (CD3-zeta and co-stimulatory domains from CD28 or 4-1BB). The engineered T cells can recognize and kill tumor cells without requiring MHC-mediated antigen presentation, bypassing one of the major tumor immune evasion mechanisms.

The manufacturing process for CAR-T therapy begins with leukapheresis, the collection of the patient's T cells from the blood. The T cells are activated, transduced with a viral vector carrying the CAR gene, expanded in culture for approximately 10 to 14 days, and infused back into the patient after a short course of lymphodepleting chemotherapy. The entire process from collection to infusion takes 3 to 5 weeks.

The first two FDA-approved CAR-T products, tisagenlecleucel (Kymriah, 2017) and axicabtagene ciloleucel (Yescarta, 2017), both target CD19, a surface protein expressed on virtually all B cell malignancies. In relapsed or refractory B cell acute lymphoblastic leukemia (ALL), tisagenlecleucel produced complete remission rates of 81 percent in patients who had failed all other treatments. In diffuse large B cell lymphoma (DLBCL), axicabtagene ciloleucel achieved complete response rates of approximately 54 percent. These results were unprecedented for patients with cancers that had been refractory to multiple prior therapies.

CAR-T therapy carries significant risks. Cytokine release syndrome (CRS) occurs when the activated CAR-T cells release massive amounts of cytokines, particularly IL-6, causing high fever, hypotension, hypoxia, and in severe cases, multi-organ failure. CRS is managed with the anti-IL-6 receptor antibody tocilizumab and corticosteroids. Immune effector cell-associated neurotoxicity syndrome (ICANS) manifests as confusion, aphasia, seizures, and, rarely, cerebral edema. Because CD19-targeted CAR-T cells eliminate normal B cells along with malignant ones, patients develop B cell aplasia and hypogammaglobulinemia that requires immunoglobulin replacement therapy.

Newer CAR-T products target BCMA (B cell maturation antigen) for multiple myeloma, with idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti) receiving FDA approval. Research is actively pursuing CAR-T therapy for solid tumors, which present additional challenges: finding tumor-specific surface targets that are not expressed on essential normal tissues, enabling CAR-T cells to infiltrate solid tumor masses, and overcoming the immunosuppressive tumor microenvironment. Targets under investigation include HER2, mesothelin, GD2, and claudin 18.2.

Cancer Vaccines and Other Approaches

Therapeutic cancer vaccines aim to stimulate the patient's own immune system to recognize and attack tumor cells. Unlike preventive vaccines (like the HPV vaccine, which prevents cervical cancer by blocking the causative virus), therapeutic vaccines target cancers that already exist. The approach involves identifying neoantigens, mutant proteins expressed by the tumor but not by normal cells, and delivering them to the immune system in a form that provokes a strong T cell response.

Personalized neoantigen vaccines are the most promising variant. The process begins with whole-exome sequencing of the patient's tumor and normal tissue to identify somatic mutations, followed by computational prediction of which mutant peptides are most likely to be presented by the patient's specific HLA molecules and recognized by T cells. These predicted neoantigens are then manufactured as synthetic peptides, RNA, or delivered via dendritic cell vaccines. Early clinical trials combining personalized neoantigen vaccines with checkpoint inhibitors have shown enhanced T cell responses and improved outcomes in melanoma and pancreatic cancer, and larger confirmatory trials are underway.

Bispecific antibodies represent another rapidly growing class of cancer immunotherapy. These engineered antibody molecules have two different binding arms: one that targets a tumor surface antigen and another that engages a T cell (typically through CD3). By physically bridging a T cell and a tumor cell, bispecific antibodies force an immunological synapse that activates the T cell and triggers tumor cell killing, regardless of the T cell's native receptor specificity. Blinatumomab (Blincyto), a CD19/CD3 bispecific, was the first approved member of this class and is used in B cell ALL. Newer bispecific formats targeting BCMA, GPRC5D, and FcRH5 are approved or in trials for multiple myeloma.

Oncolytic virus therapy uses genetically modified viruses that selectively infect and lyse tumor cells while sparing normal tissue. The virus kills tumor cells directly and also releases tumor antigens and danger signals that stimulate anti-tumor immune responses. Talimogene laherparepvec (T-VEC/Imlygic), a modified herpes simplex virus engineered to express GM-CSF, is approved for injectable melanoma lesions and produces durable responses in approximately 16 percent of patients.

Immune-Related Side Effects

By activating the immune system against cancer, immunotherapies can also trigger immune attacks against normal tissues, causing immune-related adverse events (irAEs). These side effects are fundamentally different from the nausea, hair loss, and bone marrow suppression caused by chemotherapy. Instead, they resemble autoimmune diseases: immune-mediated colitis (diarrhea, abdominal pain), hepatitis (liver inflammation), pneumonitis (lung inflammation), thyroiditis (thyroid dysfunction), hypophysitis (pituitary gland inflammation), myocarditis (heart inflammation), and dermatitis (skin rashes).

Immune-related adverse events occur in 60 to 85 percent of patients receiving checkpoint inhibitors, though most are mild to moderate (grade 1-2). Severe (grade 3-4) irAEs requiring treatment discontinuation occur in approximately 10 to 15 percent of patients on single-agent anti-PD-1 therapy and 40 to 60 percent on combination ipilimumab-nivolumab. The most dangerous irAE is immune-mediated myocarditis, which carries a mortality rate of approximately 50 percent if not recognized and treated immediately. Treatment of irAEs typically involves corticosteroids, and in severe cases, additional immunosuppressive agents like infliximab, mycophenolate mofetil, or tacrolimus.

Interestingly, the development of immune-related adverse events is correlated with better anti-tumor responses in many studies, suggesting that the same immune activation that causes irAEs is also driving tumor rejection. Managing this balance, maximizing anti-tumor immunity while minimizing autoimmune toxicity, is one of the central challenges of modern immunotherapy research.