Immunotherapy of Cancer

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 T cells which are extracted from the tumor and grown in a cell culture system with the lymphokine interleukin-2 (IL-2). The LAK cells produced 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 but this approach has not gained widespread use and is generally considered less effective than other cell therapies.

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 isolated from resected tumor tissue. This process theoretically provides a line of T cells with greater tumor specificity than those obtained from the blood. Clinical studies have shown promise (1).

Genetically modified T cells can express

• T-cell receptors (TCR) recognize tumor-associated antigens (TAAs) with high specificity to tumor cells. This approach has generally given way to CAR-T cell (see below)

• Chimeric antigen receptors (CAR) recognize specific proteins on the surface of tumor cells. CAR T cells are used for patients with B-cell lymphomas, acute lymphoblastic leukemia, and plasma cell myeloma (2, 3).

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.

Administration of exogenous antibodies constitutes passive humoral immunotherapy. Although antilymphocyte serum was 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, newer humoral immunotherapeutic modalities have been developed.

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 are effective in patients with B-cell precursor acute lymphoblastic leukemia and some other hematologic cancers. Efficacy in solid tumors is being studied (1).

Antibody-drug conjugates (ADC)3, 4).

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 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 (1).

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 (2).

Allogeneic tumor cells (cells taken from other patients) have been used in patients with acute lymphoblastic leukemia and acute myeloid leukemianonspecific 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 (3).

Messenger RNA (mRNA) vaccines were successfully used during the SARS-CoV-2 pandemic, which has sparked interest in developing them as an immunotherapeutic treatment for cancer (3).

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 4melanoma and can be used as an alternative to interferon as adjuvant treatment in high-risk melanoma (1non-small cell lung cancer (NSCLC) and other tumors (2).

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.

melanoma, non-small cell lung cancer, head and neck squamous cell cancer, kidney cancer, bladder cancer, and Hodgkin lymphoma (3, 4).

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 (5).

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 (6)

• T-cell immunoglobulin and mucin domain 3 (TIM-3), which kills helper Th1 cells (7)

• V-domain Ig suppressor of T-cell activation (VISTA), inhibition of which increases T-cell activity in tumors (8)

Bispecific antibodies that target several of these molecules together have been developed and currently are being tested in clinical trials (9).

Combinations of immune checkpoint blockers (eg, blockade of CTLA-4 and PD-1 for metastatic melanoma or advanced renal cell cancer) are under investigation. Clinical trials have demonstrated substantial clinical benefits, but combinations of immune checkpoint inhibitors are associated with higher toxicity than monotherapy (2).

Combining immunotherapy and conventional chemotherapylung cancer (10breast cancer (1110).

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 cell division and certain synthetic processes in a variety of cells, including hematopoietic stem cells.

Interferons have antitumor activity in various cancers, including hairy cell leukemia, chronic myeloid leukemia, myeloproliferative neoplasms, AIDS-associated Kaposi sarcoma, non-Hodgkin lymphoma, multiple myeloma, and ovarian cancer (1). 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 (eg, 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 and prolongation of disease-free intervals in superficial bladder cancers and may help prolong drug-induced remission in acute myeloid leukemia, ovarian cancer, and non-Hodgkin lymphoma (2).