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Immunotherapy of Cancer

By

Dmitry Gabrilovich

, MD, PhD, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania

Last full review/revision Jul 2022
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Passive Cellular Immunotherapy

In passive cellular immunotherapy, specific effector cells are directly infused and are not induced within the patient.

Lymphokine-activated killer (LAK) cells are produced from the patient’s endogenous T cells, which are extracted and grown in a cell culture system by exposing them to the lymphokine interleukin-2 (IL-2). The proliferated LAK cells are then returned to the patient’s bloodstream. Animal studies have shown that LAK cells are more effective against cancer cells than are the original endogenous T cells, presumably because of their greater number. Clinical trials of LAK cells in humans are ongoing.

Tumor-infiltrating lymphocytes (TILs) may have greater tumoricidal activity than LAK cells. These cells are grown in culture in a manner similar to LAK cells. However, the progenitor cells consist of T cells that are isolated from resected tumor tissue. This process theoretically provides a line of T cells that has greater tumor specificity than those obtained from the bloodstream. Clinical studies have shown highly promising results ( 1 Passive cellular immunotherapy reference A number of immunologic interventions, both passive and active, can be directed against tumor cells. (See also Immunotherapeutics.) In passive cellular immunotherapy, specific effector cells... read more ).

Genetically modified T cells can express

In contrast to TCR T cells, CAR T cells recognize only relatively large proteins on the surface of tumor cells. Therefore CAR T cells and TCR T cells may represent complementary approaches to cancer therapy.

Concomitant use of interferon enhances the expression of major histocompatibility complex (MHC) antigens and TAAs on tumor cells, thereby augmenting the killing of tumor cells by the infused effector cells.

Passive cellular immunotherapy reference

  • 1. Wang S, Sun J, Chen K, et al: Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors. BMC Med 19, 140 (2021). https://doi.org/10.1186/s12916-021-02006-4

Passive Humoral Immunotherapy

Administration of exogenous antibodies constitutes passive humoral immunotherapy. Antilymphocyte serum has been used in the treatment of chronic lymphocytic leukemia and in T-cell and B-cell lymphomas, resulting in temporary decreases in lymphocyte counts or lymph node size.

T-cell engagers are bispecific antibodies that recruit cytotoxic T cells to kill tumor cells. The most frequently used engagers are antibodies targeting one tumor antigen and one molecule on T cells (mostly CD3). Antibodies targeting two tumor antigens and CD3 are being tested. T-cell engagers demonstrated clinical benefits in patients with B-cell precursor acute lymphoblastic leukemia Acute Lymphoblastic Leukemia (ALL) Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated... read more Acute Lymphoblastic Leukemia (ALL) and some other hematologic malignancies. Clinical efficacy in solid tumors is under investigation.

Antibody-drug conjugates (ADC) may be used. Monoclonal antitumor antibodies may also be conjugated with different cell toxic drugs or with radioisotopes so that the antibodies deliver these toxic agents selectively to the tumor cells. For example, phase III trial of human epidermal growth factor receptor 2 (HER2)–targeting antibody conjugated with the topoisomerase I inhibitor demonstrated clinical benefits in patients with HER2-positive metastatic breast cancer ( 1 Passive humoral immunity reference A number of immunologic interventions, both passive and active, can be directed against tumor cells. (See also Immunotherapeutics.) In passive cellular immunotherapy, specific effector cells... read more ).

Passive humoral immunity reference

  • 1. Cortes J, Kim SB, Chung WP, et al: Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med 386(12):1143–1154, 2022. doi: 10.1056/NEJMoa2115022

Active Specific Immunotherapy

Inducing cellular immunity Cellular Immunity The immune response to foreign antigens consists of Humoral mechanisms (eg, antibodies) Cellular mechanisms (See also Tumor Antigens.) Most humoral responses cannot prevent tumor growth. However... read more (involving cytotoxic T cells) in a host that failed to spontaneously develop an effective response generally involves methods to enhance presentation of tumor antigens to host effector cells. Cellular immunity can be induced to specific, very well-defined antigens. Several techniques can be used to stimulate a host response; these techniques may involve giving peptides, DNA, or tumor cells (from the host or another patient). Peptides and DNA can be delivered directly, transcutaneously to myeloid or dendritic cells using electroporation or injection with adjuvants, or indirectly using antigen-presenting cells (dendritic cells). These dendritic cells can also be genetically modified to secrete additional immune-response stimulants (eg, granulocyte-macrophage colony-stimulating factor [GM-CSF]).

Peptide-based vaccines use peptides from defined TAAs. An increasing number of TAAs have been identified as the targets of T cells in cancer patients and are being tested in clinical trials. Recent data indicate that responses are most potent if the TAAs are delivered using dendritic cells. These cells are obtained from the patient, loaded with the desired TAA, and then reintroduced intradermally; they stimulate endogenous T cells to respond to the TAA. The peptides also can be delivered by co-administration with immunogenic adjuvants.

DNA vaccines use recombinant DNA that encodes a specific (defined) antigenic protein. The DNA is delivered directly via transcutaneous electroporation, incorporated into viruses that are injected directly into patients, or introduced into dendritic cells obtained from the patients, which are then injected back into them. The DNA expresses the target antigen, which triggers or enhances patients’ immune response. Clinical trials of DNA vaccines have shown promising results.

Allogeneic tumor cells (cells taken from other patients) have been used in patients with acute lymphoblastic leukemia Acute Lymphoblastic Leukemia (ALL) Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated... read more Acute Lymphoblastic Leukemia (ALL) and acute myeloid leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Acute Myeloid Leukemia (AML) . Remission is induced by intensive chemotherapy and radiation therapy. Then, irradiated allogeneic tumor cells that have been modified either genetically or chemically to increase their immunogenic potential are injected into the patient. Sometimes patients are also given bacille Calmette-Guérin (BCG) vaccine or other adjuvants (a therapeutic approach called nonspecific immunotherapy Nonspecific Immunotherapy A number of immunologic interventions, both passive and active, can be directed against tumor cells. (See also Immunotherapeutics.) In passive cellular immunotherapy, specific effector cells... read more ) to enhance the immune response against the tumor. Prolonged remissions or improved reinduction rates have been reported in some series but not in most.

Immunotherapy and Targeting Inhibitors of Immune Responses

Immune checkpoint blockers are antibodies that target molecules involved in natural inhibition of immune responses. These target molecules include the following:

  • Cytotoxic T lymphocyte-associated protein 4 (CTLA4)

  • Programmed cell death protein 1 (PD1) and programmed cell death ligands 1 (PD-L1) and 2 (PD-L2)

  • Others

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) can downregulate the activation of CD4+ and CD8+ T cells that is triggered by antigen-presenting cells (APCs). The mechanism may be the higher affinity of CTL4 for CD80 and CD86 (costimulatory receptors) than the costimulatory receptor CD28 on APCs. CTLA-4 is upregulated by activation of T cell receptor and by cytokines such as interferon-gamma and interleukin-12. The CTLA-4 inhibitor ipilimumab prolongs survival in metastatic melanoma Melanoma Malignant melanoma arises from melanocytes in a pigmented area (eg, skin, mucous membranes, eyes, or central nervous system). Metastasis is correlated with depth of dermal invasion. With spread... read more Melanoma and can be used as an alternative to interferon as adjuvant treatment in high-risk melanoma. Tremelimumab, another CTLA-4 inhibitor, is being studied in mesothelioma Mesothelioma Pleural mesothelioma is the only known pleural cancer and is caused by asbestos exposure in nearly all cases. Diagnosis is based on history and chest x-ray or CT findings and tissue biopsy.... read more Mesothelioma and other tumors.

PD-1 and PD ligand 1 and 2 inhibitors can counteract certain immune inhibitory effects triggered by the interaction of PD-1 and PD-L1 or PD-L2. PD-1 is expressed on T cells, B cells, natural killer (NK) cells, and some others (eg, monocytes, dendritic cells). It binds to PD-L1 (expressed on many tumor cells, hematopoietic cells, and some other cells) and PD-L2 (expressed mainly on hematopoietic cells). This binding inhibits tumor cell apoptosis and facilitates T-cell exhaustion and the conversion of T-cell cytotoxic and helper T cells to regulatory T cells. PD-1 and PD-L1/2 are upregulated by cytokines such as interleukin-12 and interferon-gamma in the tumor microenvironment and prevent T-cell activation and recognition of tumor cells.

Nivolumab and pembrolizumab are IgG4 PD-1 inhibitors that increase T-cell activation and infiltration of tumors and prolong survival in metastatic melanoma Melanoma Malignant melanoma arises from melanocytes in a pigmented area (eg, skin, mucous membranes, eyes, or central nervous system). Metastasis is correlated with depth of dermal invasion. With spread... read more Melanoma , non-small cell lung cancer Lung Carcinoma Lung carcinoma is the leading cause of cancer-related death worldwide. About 85% of cases are related to cigarette smoking. Symptoms can include cough, chest discomfort or pain, weight loss... read more Lung Carcinoma , head and neck squamous cell carcinoma Oropharyngeal Squamous Cell Carcinoma Oropharyngeal squamous cell carcinoma refers to cancer of the tonsil, base and posterior one third of the tongue, soft palate, and posterior and lateral pharyngeal walls. Squamous cell carcinoma... read more , kidney cancer Renal Cell Carcinoma Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more , bladder cancer Bladder Cancer Bladder cancer is usually transitional cell (urothelial) carcinoma. Patients usually present with hematuria (most commonly) or irritative voiding symptoms such as frequency and/or urgency; later... read more Bladder Cancer , and Hodgkin lymphoma Hodgkin Lymphoma Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Hodgkin Lymphoma . Clinical trials continue on the use of these drugs in the treatment of other cancers.

Lymphocyte activator gene 3 (LAG-3) increases T cell regulator activity by interacting with MHC on tumor cells. Blockade of LAG3 with monoclonal antibody has demonstrated strong clinical benefit in patients with unresectable metastatic melanoma ( 1 Pearls & Pitfalls Pearls & Pitfalls ).

Others targeting inhibitors under study are generally in earlier stages of clinical development. These include, for example, B and T cell lymphocyte attenuator (BTLA), which decreases production of cytokines and CD4 cell proliferation; T-cell immunoglobulin and mucin domain 3 (TIM-3), which kill helper Th1 cells; and V-domain Ig suppressor of T-cell activation (VISTA), inhibition of which increases T-cell activity in tumors. In recent years, bispecific antibodies targeting several of these molecules together have been developed and currently are being tested in clinical trials.

Combinations of immune checkpoint blockers (eg, blockade of CTLA-4 and PD-1 for metastatic melanoma or advanced renal cell carcinoma) are under investigation. Clinical trials have demonstrated substantial clinical benefits but are associated with higher toxicity than single therapy.

Combining immunotherapy and conventional chemotherapy is a novel approach to cancer treatment. It has shown some success (vs historic controls) in nonrandomized phase I and phase II clinical trials involving various cancers, types of vaccines, and chemotherapy. The combination of the checkpoint inhibitor pembrolizumab with chemotherapy is used as first-line treatment of metastatic squamous non–small cell lung cancer Lung Carcinoma Lung carcinoma is the leading cause of cancer-related death worldwide. About 85% of cases are related to cigarette smoking. Symptoms can include cough, chest discomfort or pain, weight loss... read more Lung Carcinoma ( 2 Immunotherapy and immune inhibitors references A number of immunologic interventions, both passive and active, can be directed against tumor cells. (See also Immunotherapeutics.) In passive cellular immunotherapy, specific effector cells... read more ). The combination of the check-point inhibitor atezolizumab with chemotherapy can be used to treat patients with triple-negative breast cancer Breast Cancer Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more Breast Cancer ( 3 Pearls & Pitfalls Pearls & Pitfalls ). The PD-L1 check-point inhibitor durvalumab in combination with chemotherapy has demonstrated efficacy in patients with small cell lung cancer and after conventional chemotherapy in patients with non-small cell lung cancer ( 4 Pearls & Pitfalls Pearls & Pitfalls ).

Immunotherapy and immune inhibitors references

  • 1. Tawbi HA, Schadendorf D, Lipson EJ, et al: Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med 386(1):24–34, 2022. doi: 10.1056/NEJMoa2109970

  • 2. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092, 2018. doi: 10.1056/NEJMoa1801005

  • 3. Schmid P, Adams S, Rugo HS, et al: Atezolizumab and Nab-Paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379(22):2108–2121, 2018 . doi: 10.1056/NEJMoa1809615

  • 4. Paz-Ares L, Dvorkin M, Chen Y, et al: Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 394(10212):1929–1939, 2019. doi: 10.1016/S0140-6736(19)32222-6

Nonspecific Immunotherapy

Interferons (IFN-alpha, IFN-beta, IFN-gamma) are glycoproteins that have antitumor and antiviral activity. Depending on dose, interferons may either enhance or decrease cellular immune function and humoral immune function Host Response to Tumors The immune response to foreign antigens consists of Humoral mechanisms (eg, antibodies) Cellular mechanisms (See also Tumor Antigens.) Most humoral responses cannot prevent tumor growth. However... read more . Interferons also inhibit cell division and certain synthetic processes in a variety of cells, including hematopoietic stem cells.

Clinical trials have shown that interferons have antitumor activity in various cancers, including hairy cell leukemia, chronic myeloid leukemia Chronic Myeloid Leukemia (CML) Chronic myeloid leukemia (CML) occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of mature and immature... read more , myeloproliferative neoplasms Overview of Myeloproliferative Neoplasms Myeloproliferative neoplasms are clonal proliferations of bone marrow stem cells, which can manifest as an increased number of platelets, red blood cells (RBCs), or white blood cells (WBCs)... read more , AIDS-associated Kaposi sarcoma Kaposi Sarcoma Kaposi sarcoma is a multicentric vascular tumor caused by herpesvirus type 8. It can occur in classic, AIDS-associated, endemic (in Africa), and iatrogenic (eg, after organ transplantation)... read more Kaposi Sarcoma , non-Hodgkin lymphoma Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more Non-Hodgkin Lymphomas , multiple myeloma Multiple Myeloma Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more Multiple Myeloma , and ovarian carcinoma Ovarian, Fallopian Tube, and Peritoneal Cancer Ovarian cancer is often fatal because it is usually advanced when diagnosed. The most common histology—high-grade serous epithelial ovarian cancer—is considered as a single clinical entity along... read more . However, interferons can have significant adverse effects, such as fever, malaise, leukopenia, alopecia, myalgia, cognitive and depressive effects, cardiac arrhythmias, and hypothyroidism.

Certain bacterial adjuvants (bacille Calmette–Guérin [BCG] and derivatives, killed suspensions of Corynebacterium parvum) have tumoricidal properties. They have been used with or without added tumor antigen to treat a variety of cancers, usually along with intensive chemotherapy or radiation therapy. For example, direct injection of BCG into cancerous tissues has resulted in regression of melanoma Melanoma Malignant melanoma arises from melanocytes in a pigmented area (eg, skin, mucous membranes, eyes, or central nervous system). Metastasis is correlated with depth of dermal invasion. With spread... read more Melanoma and prolongation of disease-free intervals in superficial bladder carcinomas Superficial cancers Bladder cancer is usually transitional cell (urothelial) carcinoma. Patients usually present with hematuria (most commonly) or irritative voiding symptoms such as frequency and/or urgency; later... read more Superficial cancers and may help prolong drug-induced remission in acute myeloid leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more Acute Myeloid Leukemia (AML) , ovarian carcinoma Ovarian, Fallopian Tube, and Peritoneal Cancer Ovarian cancer is often fatal because it is usually advanced when diagnosed. The most common histology—high-grade serous epithelial ovarian cancer—is considered as a single clinical entity along... read more , and non-Hodgkin lymphoma Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more Non-Hodgkin Lymphomas .

Drugs Mentioned In This Article

Drug Name Select Trade
YERVOY
OPDIVO
KEYTRUDA
TECENTRIQ
IMFINZI
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