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Immunotherapy of Cancer

By Dmitry Gabrilovich, MD, PhD, Christopher M. Davis Professor in Cancer Research, Program Leader, Translational Tumor Immunology;Professor, The Wistar Institute;Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania

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A number of immunologic interventions, both passive and active, can be directed against tumor cells.

Passive Cellular Immunotherapy

In passive cellular immunotherapy, specific effector cells are directly infused and are not induced or expanded 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. Recent clinical studies have shown highly promising results.

Genetically modified T cells can express

  • T-cell receptors (TCR) that recognize tumor-associated antigens (TAAs) with high specificity to tumor cells: This approach is under study and may provide significant clinical benefit. Results of initial trials are encouraging.

  • Chimeric antigen receptors (CAR) that recognize specific proteins on the surface of tumor cells: This approach has demonstrated great potential in clinical trials in patients with B-cell leukemia.

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 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.

Monoclonal antitumor antibodies may also be conjugated with toxins (eg, ricin, diphtheria) or with radioisotopes so that the antibodies deliver these toxic agents specifically to the tumor cells. Another technique involves bispecific antibodies, or linkage of one antibody that reacts with the tumor cell to a second antibody that reacts with a cytotoxic effector cell. This technique brings the effector cell in close opposition to the tumor cell, resulting in increased tumoricidal activity. However, these techniques are in early stages of testing; thus, potential clinical benefits are uncertain.

Active Specific Immunotherapy

Inducing cellular immunity (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 are often given 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 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 incorporated into viruses that are injected directly into patients or, more often, 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.

Autochthonous tumor cells (cells taken from the patient) have been reintroduced to the patient after use of ex vivo techniques (eg, irradiation, neuraminidase treatment, hapten conjugation, hybridization with other cell lines) to reduce their malignant potential and increase their antigenic activity. Sometimes the tumor cells are genetically modified to produce immunostimulatory molecules (including cytokines such as GM-CSF or interleukin 2 (IL-2), costimulatory molecules such as B7-1, and allogeneic class I MHC molecules); this modification helps attract effector molecules and enhances systemic tumor targeting. Clinical trials with GM-CSF–modified tumor cells have produced encouraging preliminary results.

Allogeneic tumor cells (cells taken from other patients) have been used in patients with acute lymphocytic leukemia and acute myelogenous leukemia. 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 (see Immunotherapy of Cancer: Nonspecific Immunotherapy) to enhance the immune response against the tumor. Prolonged remissions or improved reinduction rates have been reported in some series but not in most.

A novel approach to cancer treatment combining immunotherapy and conventional chemotherapy has shown some success (vs historic controls) in nonrandomized phase I and phase II clinical trials involving various cancers, types of vaccines, and chemotherapy.

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 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 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 (expressed on T cells, B cells, natural killer (NK) cells, and some others (eg, monocytes, dendritic cells) 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. Nivolumab and pembrolizumab are IgG4 PD-1 inhibitors that prolong survival in metastatic melanoma and non-small cell lung cancer. They are also in phase III clinical trials as treatment for other cancers (eg, lymphomas, head and neck cancer, renal cell carcinoma, certain colorectal carcinomas).

Others 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), lymphocyte activator gene 3 (LAG3, which increases T cell regulator activity), T cell immunoglobulin and mucin domain 3 (TIM-3, which kills helper Th1 cells), and V-domain Ig suppressor of T cell activation (VISTA, inhibition of which increases T cell activity in tumors).

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. Interferons also inhibit division and certain synthetic processes in a variety of cells. Clinical trials have indicated that interferons have antitumor activity in various cancers, including hairy cell leukemia, chronic myelogenous leukemia, myeloproliferative neoplasms, AIDS-associated Kaposi sarcoma, non-Hodgkin lymphoma, multiple myeloma, and ovarian carcinoma. However, interferons may have significant adverse effects, such as fever, malaise, leukopenia, alopecia, and myalgias.

Certain bacterial adjuvants (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 and prolongation of disease-free intervals in superficial bladder carcinomas and may help prolong drug-induced remission in acute myelogenous leukemia, ovarian carcinoma, and non-Hodgkin lymphoma.

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