| Cancer immunotherapy | |
|---|---|
 | |
| Specialty | Tumor immunology |
Cancer immunotherapy (immuno-oncotherapy) is the stimulation of theimmune system to treatcancer, improving the immune system's natural ability to fight the disease.[1] It is an application of thefundamental research ofcancer immunology (immuno-oncology) and a growing subspecialty ofoncology.
Cancer immunotherapy exploits the fact thatcancer cells often havetumor antigens, molecules on their surface that can bind toantibody proteins orT-cell receptors, triggering an immune system response. The tumorantigens are oftenproteins or other macromolecules (e.g.,carbohydrates). Normal antibodies bind to external pathogens, but the modifiedimmunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill. The clinical success of cancer immunotherapy is highly variable between different forms of cancer; for instance, certain subtypes ofgastric cancer react well to the approach whereas immunotherapy is not effective for other subtypes.[2]
Major types of cancer immunotherapy include immunecheckpoint inhibitors, which block inhibitory pathways such asPD-1/PD-L1 andCTLA-4 to enhanceT cell activity against tumors. These therapies have shown effectiveness in treating cancers such asmelanoma andlung cancer.[3][4][5]
Adoptive cell therapies, includingchimeric antigen receptor (CAR) T cell therapy, involve modifying a patient's immune cells to recognize cancer-specific antigens. These therapies have been particularly effective in certain blood cancers.[4][5][6]Natural killer cell (NK) therapies and CAR-NK cell approaches are also being explored, leveraging NK cells' innate ability to target tumor cells.[5][6] Other strategies includecancer vaccines, which aim to provoke an immune response againsttumor-associated antigens, and may be either preventive or therapeutic.[5] Immunomodulatory agents such ascytokines (e.g.,interleukin-2,interferon-alpha) andBacillus Calmette-Guerin (BCG) are used to enhance immune activity or alter the tumor microenvironment.[5]Oncolytic virus therapies, which employ engineered viruses to selectively kill cancer cells while promoting systemic immunity, are also under investigation.[3]
In 2018, American immunologistJames P. Allison and Japanese immunologistTasuku Honjo received theNobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation.[7]
"During the 17th and 18th centuries, various forms of immunotherapy in cancer became widespread... In the 18th and 19th centuries, septic dressings enclosing ulcerative tumours were used for the treatment of cancer. Surgical wounds were left open to facilitate the development of infection, and purulent sores were created deliberately... One of the most well-known effects of microorganisms on ... cancer was reported in 1891, when an American surgeon,William Coley, inoculated patients having inoperable tumours with [Streptococcus pyogenes ]."[8] "Coley [had] thoroughly reviewed the literature available at that time and found 38 reports of cancer patients with accidental oriatrogenic feverisherysipelas. In 12 patients, the sarcoma or carcinoma had completely disappeared; the others had substantially improved. Coley decided to attempt the therapeutic use of iatrogenic erysipelas..."[9] "Coley developed a toxin that contained heat-killed bacteria [Streptococcus pyogenes andSerratia marcescens ]. Until 1963, this treatment was used for the treatment of sarcoma."[8] "Coley injected more than 1000 cancer patients with bacteria or bacterial products."[10] 51.9% of [Coley's] patients with inoperable soft-tissue sarcomas showed complete tumour regression and survived for more than 5 years, and 21.2% of the patients had no clinical evidence of tumour at least 20 years after this treatment..."[8] Research continued in the 20th century under Maria O'Connor Hornung atTulane Medical School.[11][12]
In the 1980's, researchers at theNational Cancer Institute's Center for Cancer Research (CCR) began exploring the then-heretical idea that a patient's immune system could be harnessed to fight cancer. These researchers includedMichael Potter,Ira Pastan, andSteven Rosenberg who developed approaches includingmonoclonal antibody-basedimmunotoxins,checkpoint blockade drugs,cytokine-based therapies, andadoptive cell therapy studies.[13]
There are several types of immunotherapy used to treat cancer:[14][15]
Immunotherapies can be categorized as active or passive based on their ability to engage the host immune system against cancer.[16][17] Active immunotherapy specifically targets tumor cells via the immune system. Examples include therapeutic cancer vaccines (also known as treatment vaccines,[18] which are designed to boost the body's immune system to fight cancer),CAR-T cells, and targeted antibody therapies. In contrast, passive immunotherapy does not directly target tumor cells, but enhances the ability of the immune system to attack cancer cells. Examples includecheckpoint inhibitors andcytokines.[citation needed]
Active cellular therapies aim to destroy cancer cells by recognition of distinct markers known asantigens. In cancer vaccines, the goal is to generate an immune response to these antigens through a vaccine. Currently, only one vaccine (sipuleucel-T for prostate cancer) has been approved. In cell-mediated therapies like CAR-T cell therapy, immune cells are extracted from the patient,genetically engineered to recognize tumor-specific antigens, and returned to the patient. Cell types that can be used in this way arenatural killer (NK) cells,lymphokine-activated killer cells,cytotoxic T cells, anddendritic cells. Finally, specific antibodies can be developed that recognize cancer cells and target them for destruction by the immune system. Examples of such antibodies includerituximab (targeting CD-20),trastuzumab (targeting HER-2), andcetuximab (targeting EGFR).[citation needed]
Passive antibody therapies aim to increase the activity of the immune system without specifically targeting cancer cells. For example, cytokines directly stimulate the immune system and increase immune activity. Checkpoint inhibitors target proteins (immune checkpoints) that normally dampen the immune response. This enhances the ability of the immune system to attack cancer cells. Current research is identifying new potential targets to enhance immune function. Approved checkpoint inhibitors include antibodies such asipilimumab,nivolumab, andpembrolizumab.[citation needed]
Dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. Dendritic cells areantigen-presenting cells (APCs) in the mammalian immune system.[19] In cancer treatment, they aid cancer antigen targeting.[20] The only approved cellular cancer therapy based on dendritic cells issipuleucel-T.[citation needed]
One method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates[21] or short peptides (small parts of the protein that correspond to the protein antigens on cancer cells). These peptides are often given in combination withadjuvants (highlyimmunogenic substances) to increase the immune and anti-tumor responses. Other adjuvants include proteins or other chemicals that attract and/or activate dendritic cells, such asgranulocyte-macrophage colony-stimulating factor (GM-CSF). The most common sources of antigens used for dendritic cell vaccine inglioblastoma (GBM) as an aggressive brain tumor were whole tumor lysate, CMV antigen RNA and tumor-associated peptides likeEGFRvIII.[22]
Dendritic cells can also be activatedin vivo by making tumor cells express GM-CSF. This can be achieved by either genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with anoncolytic virus that expresses GM-CSF.[citation needed]
Another strategy is to remove dendritic cells from the blood of a patient and activate them outside the body. The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumorcell lysate (a solution of broken-down tumor cells). These cells (with optional adjuvants) are infused and provoke an immune response.[citation needed]
Dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such asTLR3,TLR7,TLR8 orCD40 have been used as antibody targets.[20] Dendritic cell-NK cell interface also has an important role in immunotherapy. The design of new dendritic cell-based vaccination strategies should also encompass NK cell-stimulating potency. It is critical to systematically incorporate NK cells monitoring as an outcome in antitumor DC-based clinical trials.[citation needed]
Sipuleucel-T (Provenge) was approved for treatment of asymptomatic or minimally symptomatic metastatic castration-resistantprostate cancer in 2010. The treatment consists of removal ofantigen-presenting cells from blood byleukapheresis and growing them with thefusion protein PA2024 made from GM-CSF and prostate-specificprostatic acid phosphatase (PAP) and reinfused. This process is repeated three times.[23][24][25][26]
Adoptive T cell therapy is a form ofpassive immunization by the transfusion of T-cells. They are found in blood and tissue and typically activate when they find foreignpathogens. Activation occurs when the T-cell's surface receptors encounter cells that display parts of foreign proteins (either on their surface or intracellularly). These can be either infected cells or otherantigen-presenting cells (APCs). The latter are found in normal tissue and in tumor tissue, where they are known astumor-infiltrating lymphocytes (TILs). They are activated by the presence of APCs such as dendritic cells that presenttumor antigens. Although these cells can attack tumors, thetumor microenvironment is highly immunosuppressive, interfering with immune-mediated tumour death.[27]
Multiple ways of producing tumour-destroying T-cells have been developed. Most commonly, T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. The T-cells can optionally be modified in various ways, cultured and infused into patients. T cells can be modified via genetic engineering, producing CAR-T cell or TCR T cells or by exposing the T cells to tumor antigens in a non-immunosuppressive environment, that they recognize as foreign and learn to attack.[citation needed]
Another approach is transfer of haploidenticalγδ T cells ornatural killer cells from a healthy donor.[28] The major advantage of this approach is that these cells do not causegraft-versus-host disease. The disadvantage is that transferred cells frequently have impaired function.[29]
The simplest example involves removing TILs from a tumor, culturing but not modifying them, and infusing the result back into the tumour. The first therapy of this type,Lifileucel, achieved USFood and Drug Administration (FDA) approval in February 2024.[citation needed]
The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to target and destroy them. Scientists harvest T cells from people, genetically alter them to add a chimeric antigen receptor (CAR) that specifically recognizes cancer cells, then infuse the resulting CAR-T cells into patients to attack their tumors.[citation needed]
Tisagenlecleucel (Kymriah), achimeric antigen receptor (CAR-T) therapy, was approved by the FDA in 2017 to treatacute lymphoblastic leukemia (ALL).[30] This treatment removesCD19 positive cells (B-cells) from the body (including the diseased cells, but also normal antibody-producing cells).[citation needed]
Axicabtagene ciloleucel (Yescarta) is another CAR-T therapeutic, approved in 2017 for treatment ofdiffuse large B-cell lymphoma (DLBCL).[31]
Multifunctional alginate scaffolds for T cell engineering and release (MASTER) is a technique forin situ engineering, replication and release of genetically engineered T cells. It is an evolution ofCAR T cell therapy. T cells are extracted from the patient and mixed with a genetically engineered virus that contains a cancer-targeting gene (as with CAR T). The mixture is then added to a MASTER (scaffold), which absorbs them. The MASTER containsantibodies that activate the T cells andinterleukins that trigger cell proliferation. The MASTER is then implanted into the patient. The activated T cells interact with the viruses to become CAR T cells. The interleukins stimulate these CAR T cells to proliferate, and the CAR T cells exit the MASTER to attack the cancer. The technique takes hours instead of weeks. And because the cells are younger, they last longer in the body, show stronger potency against cancer, and display fewer markers of exhaustion. These features were demonstrated in mouse models. The treatment was more effective and longer-lasting againstlymphoma.[32][33]
T cell receptor T cell therapy (TCR-T) is a type ofadoptive T-cell therapy that targets some cancers. TCR-T therapies are based on the use and redirection of theT cell receptor (TCR) against specific antigen of interest such as a tumor antigens.[34] TCRs areheterodimers made of alpha and betapeptide chains to recognizeMHC-presentedpolypeptide fragment molecules.[35] Unlike CAR-T, which uses cell surface antigens, TCR-T can recognize MHC's larger set of intracellular antigen fragments. However, TCR-T cell therapy depends on MHC molecules, limiting its usefulness.[34][36][37]
Each T cell's TCR is specific to one antigen and sits on the T cell's surface. The affinity of human TCRs to tumor antigens is relatively low, rendering them unable to recognize and kill tumor cells effectively. The modified T cell has much higher affinity, which enhances both recognition and affinity supporting the recognition of tumor cells.[36]
Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that bindsspecifically to almost anyextracellular target, such ascell surface proteins andcytokines. They can be used to render their target ineffective (e.g. by preventing receptor binding),[38] to induce a specific cell signal (by activating receptors),[38] to cause theimmune system to attack specific cells, or to bring a drug to a specific cell type (such as withradioimmunotherapy which deliverscytotoxic radiation).
Two types are used in cancer treatments:[39]
Fc's ability to bindFc receptors is important because it allows antibodies to activate the immune system. Fc regions are varied: they exist in numerous subtypes and can be further modified, for example with the addition of sugars in a process calledglycosylation. Changes in theFc region can alter an antibody's ability to engage Fc receptors and, by extension, will determine the type of immune response that the antibody triggers.[42] For example,immune checkpoint blockers targeting PD-1 are antibodies designed to bind PD-1 expressed by T cells and reactivate these cells to eliminatetumors.[43]Anti-PD-1 drugs contain not only a Fab region that binds PD-1 but also an Fc region. Experimental work indicates that the Fc portion of cancer immunotherapy drugs can affect the outcome of treatment. For example, anti-PD-1 drugs with Fc regions that bind inhibitory Fc receptors can have decreased therapeutic efficacy.[44] Imaging studies have further shown that the Fc region of anti-PD-1 drugs can bind Fc receptors expressed by tumor-associated macrophages. This process removes the drugs from their intended targets (i.e. PD-1 molecules expressed on the surface of T cells) and limits therapeutic efficacy.[45] Furthermore, antibodies targeting the co-stimulatory proteinCD40 require engagement with selective Fc receptors for optimal therapeutic efficacy.[46] Together, these studies underscore the importance of Fc status in antibody-basedimmune checkpoint targeting strategies.[citation needed]
Antibodies can come from a variety of sources, including human cells, mice, and a combination of the two (chimeric antibodies). Different sources of antibodies can provoke different kinds of immune responses. For example, the human immune system can recognize mouse antibodies (also known as murine antibodies) and trigger an immune response against them. This could reduce the effectiveness of the antibodies as a treatment and cause an immune reaction. Chimeric antibodies attempt to reduce murine antibodies'immunogenicity by replacing part of the antibody with the corresponding human counterpart. Humanized antibodies are almost completely human; only thecomplementarity determining regions of thevariable regions are derived from murine sources. Human antibodies have been produced using unmodified human DNA.[40]
Antibody-dependent cell-mediated cytotoxicity (ADCC) requires antibodies to bind to target cell surfaces. Antibodies are formed of a binding region (Fab) and the Fc region that can be detected by immune system cells via theirFc surface receptors. Fc receptors are found on many immune system cells, including NK cells. When NK cells encounter antibody-coated cells, the latter's Fc regions interact with their Fc receptors, releasingperforin andgranzyme B to kill the tumor cell. Examples includerituximab,ofatumumab,elotuzumab, andalemtuzumab. Antibodies under development have altered Fc regions that have higher affinity for a specific type of Fc receptor, FcγRIIIA, which can dramatically increase effectiveness.[47][48]
Many tumor cells overexpressCD47 to escapeimmunosurveilance of host immune system. CD47 binds to its receptorsignal-regulatory protein alpha (SIRPα) and downregulatephagocytosis of tumor cell.[49] Therefore, anti-CD47 therapy aims to restore clearance of tumor cells. Additionally, growing evidence supports the employment of tumor antigen-specificT cell response in response to anti-CD47 therapy.[50][51] A number of therapeutics are being developed, including anti-CD47antibodies, engineereddecoy receptors, anti-SIRPαantibodies and bispecific agents.[50] As of 2017, wide range of solid and hematologic malignancies were being clinically tested.[50][52]
Carbohydrateantigens on the surface of cells can be used as targets for immunotherapy.GD2 is aganglioside found on the surface of many types of cancer cell includingneuroblastoma,retinoblastoma,melanoma,small cell lung cancer,brain tumors,osteosarcoma,rhabdomyosarcoma,Ewing's sarcoma,liposarcoma,fibrosarcoma,leiomyosarcoma and othersoft tissue sarcomas. It is not usually expressed on the surface of normal tissues, making it a good target for immunotherapy. As of 2014, clinical trials were underway.[53]
Thecomplement system includes blood proteins that can cause cell death after an antibody binds to the cell surface (theclassical complement pathway, among the ways of complement activation). Generally, the system deals with foreign pathogens but can be activated with therapeutic antibodies in cancer. The system can be triggered if the antibody is chimeric, humanized, or human; as long as it contains theIgG1Fc region. Complement can lead to cell death by activation of themembrane attack complex, known as complement-dependentcytotoxicity; enhancement ofantibody-dependent cell-mediated cytotoxicity; and CR3-dependent cellular cytotoxicity. Complement-dependent cytotoxicity occurs when antibodies bind to the cancer cell surface, the C1 complex binds to these antibodies and subsequently, protein pores are formed in cancercell membrane.[54]
Blocking
Antibody therapies can also function by binding to proteins and physically blocking them from interacting with other proteins. Checkpoint inhibitors (CTLA-4, PD-1, and PD-L1) operate by this mechanism. Briefly, checkpoint inhibitors are proteins that normally help to slow immune responses and prevent the immune system from attacking normal cells. Checkpoint inhibitors bind these proteins and prevent them from functioning normally, which increases the activity of the immune system. Examples includedurvalumab,ipilimumab,nivolumab, andpembrolizumab.[55]
| Antibody | Brand name | Type | Target | Approval date | Approved treatment(s) |
|---|---|---|---|---|---|
| Alemtuzumab | Campath | humanized | CD52 | 2001 | B-cellchronic lymphocytic leukemia (CLL)[57] |
| Atezolizumab | Tecentriq | humanized | PD-L1 | 2016 | bladder cancer[58] |
| Atezolizumab/hyaluronidase | Tecentriq Hybreza | humanized | PD-L1 | 2024 | non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma[59][60][61] |
| Avelumab | Bavencio | human | PD-L1 | 2017 | metastatic Merkel cell carcinoma[62] |
| Durvalumab | Imfinzi | human | PD-L1 | 2017 | bladder cancer[63] non-small cell lung cancer[64] |
| Elotuzumab | Empliciti | humanized | SLAMF7 | 2015 | multiple myeloma[65] |
| Ipilimumab | Yervoy | human | CTLA4 | 2011 | metastaticmelanoma[66] |
| Nivolumab | Opdivo | human | PD-1 | 2014 | unresectable ormetastatic melanoma,squamous non-small cell lung cancer, Renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, classical hodgkin lymphoma[67][68] |
| Ofatumumab | Arzerra | human | CD20 | 2009 | refractoryCLL[69] |
| Pembrolizumab | Keytruda | humanized | PD-1 | 2014 | unresectable ormetastatic melanoma,squamous non-small cell lung cancer (NSCLC),[70]Hodgkin's lymphoma,[71]Merkel-cell carcinoma (MCC),[72]primary mediastinal B-cell lymphoma (PMBCL),[73]stomach cancer,cervical cancer[74] |
| Rituximab | Rituxan, Mabthera | chimeric | CD20 | 1997 | non-Hodgkin lymphoma[75] |
| Rituximab/hyaluronidase | Rituxan Hycela | chimeric | CD20 | 2017 | follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia[76] |
| Trastuzumab | Rituxan Hycela | humanized | HER2/neu | 1998 | breast cancer, gastric or gastroesophageal junction adenocarcinoma |
Alemtuzumab (Campath-1H) is an anti-CD52 humanized IgG1 monoclonal antibody indicated for the treatment offludarabine-refractorychronic lymphocytic leukemia (CLL),cutaneous T-cell lymphoma,peripheral T-cell lymphoma andT-cell prolymphocytic leukemia. CD52 is found on >95% of peripheral bloodlymphocytes (both T-cells and B-cells) andmonocytes, but its function in lymphocytes is unknown. It binds to CD52 and initiates its cytotoxic effect by complement fixation and ADCC mechanisms. Due to the antibody target (cells of the immune system), common complications of alemtuzumab therapy are infection, toxicity andmyelosuppression.[77][78][79]
Atezolizumab, sold under the brand name Tecentriq among others, is amonoclonal antibody medication used to treaturothelial carcinoma,non-small cell lung cancer (NSCLC),small cell lung cancer (SCLC),hepatocellular carcinoma andalveolar soft part sarcoma,[80][81] but discontinued for use intriple-negative breast cancer (TNBC).[82] It is a fullyhumanized, engineeredmonoclonal antibody ofIgG1isotype against the proteinprogrammed cell death-ligand 1 (PD-L1).[83]
The most common side effects when used on its own include tiredness, reduced appetite, nausea, vomiting, cough, difficulty breathing, diarrhea, rash, fever, pain in the back, joints, muscles and bones, weakness, itching andurinary tract infection.[84] The most common side effects when used with other cancer medicines includeperipheral neuropathy (nerve damage in the hands and feet), nausea,anemia (low red blood cell counts),neutropenia (low white blood cell counts),thrombocytopenia (low platelet counts), rash, tiredness, constipation, reduced appetite, diarrhea, and cough.[84]
Atezolizumab was the first PD-L1 inhibitor approved by the USFood and Drug Administration (FDA) for bladder cancer.[85] In the European Union, atezolizumab is the first PD-(L)1 cancer immunotherapy for subcutaneous injection.[86] Atezolizumab is a therapeutic alternative on theWorld Health Organization's List of Essential Medicines.[87]
Atezolizumab/hyaluronidase, sold under the brand name Tecentriq Hybreza, is afixed-dose combination medication used for the treatment of non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma.[88][89] It containsatezolizumab, a programmed death-ligand 1 (PD-L1) blocking monoclonal antibody; andhyaluronidase (human recombinant), anendoglycosidase.[88] It is taken bysubcutaneous injection.[88]
The most common adverse reactions include fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.[88][89]
Atezolizumab/hyaluronidase was approved for medical use in the United States in September 2024.[88][89][90][91]
Avelumab, sold under the brand name Bavencio, is a fully humanmonoclonal antibody medication for the treatment ofMerkel cell carcinoma,urothelial carcinoma, andrenal cell carcinoma.[92]
Common side effects include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reactions, rash, decreased appetite and swelling of the limbs (peripheral edema).[93]
Avelumab targets the proteinprogrammed death-ligand 1 (PD-L1). It has receivedorphan drug designation by theEuropean Medicines Agency (EMA) for the treatment ofgastric cancer in January 2017.[94] The USFood and Drug Administration (FDA) approved it in March 2017, for the treatment ofMerkel-cell carcinoma,[93] an aggressive type of skin cancer. The EMA approved it in September 2017, for the same indication.[95] This is the first FDA-approved treatment for metastatic Merkel-cell carcinoma, a rare, aggressive form of skin cancer.[93] Avelumab was developed byMerck KGaA andPfizer.[96]
Durvalumab (Imfinzi) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules. Durvalumab is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:[citation needed]
On 16 February 2018, the Food and Drug Administration approved durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.[97]
Elotuzumab, sold under the brand name Empliciti, is a humanized IgG1monoclonal antibody medication used in combination withlenalidomide anddexamethasone, for adults that have received 1 to 3 prior therapies for the treatment ofmultiple myeloma.[98] It is also indicated for adult patients in combination withpomalidomide anddexamethasone, who have received 2 prior therapies including lenalidomide and aprotease inhibitor.[98] Administration of elotuzumab is doneintravenously.[98] Each intravenous injection of elotuzumab should be premedicated withdexamethasone,diphenhydramine,ranitidine andacetaminophen.[99] It is being developed byBristol Myers Squibb andAbbVie.[100]
Commonside effects of elotuzumab with lenalidomide and dexamethasone includesfatigue,diarrhea,pyrexia,constipation,cough,peripheral neuropathy,nasopharyngitis,upper respiratory tract infection, decreased appetite, andpneumonia.[98] The most common side effects of elotuzumab with pomalidomide and dexamethasone includesconstipation andhyperglycemia.[98] There is no available information for the use of elotuzumab inpregnant women.[98]
Elotuzumab is animmunostimulatory antibody that targets the Signaling Lymphocytic Activation Molecule Family member 7 (SLAMF7) through two mechanisms.[98]
In May 2014, it was grantedbreakthrough therapy designation by the USFood and Drug Administration (FDA) (for multiple myeloma).[101] The initialFDA approval of elotuzumab in 2015 in combination withlenalidomide anddexamethasone was carried out through the results illustrated in the ELOQUENT 2 study.[102] In May 2016 the EC/EU gave a similar approval.[103] Furthermore, the results of the ELOQUENT 3 study led to theFDA approval of elotuzumab in combination withpomalidomide anddexamethasone in 2018.[104]
Ipilimumab (Yervoy) is a humanIgG1 antibody that binds the surface proteinCTLA4. In normal physiology T-cells are activated by two signals: theT-cell receptor binding to anantigen-MHC complex and T-cell surface receptor CD28 binding toCD80 orCD86 proteins. CTLA4 binds to CD80 or CD86, preventing the binding of CD28 to these surface proteins and therefore negatively regulates the activation of T-cells.[105][106][107][108]
Activecytotoxic T-cells are required for the immune system to attack melanoma cells. Normally inhibited active melanoma-specific cytotoxic T-cells can produce an effective anti-tumor response. Ipilimumab can cause a shift in the ratio ofregulatory T-cells to cytotoxic T-cells to increase the anti-tumor response. Regulatory T-cells inhibit other T-cells, which may benefit the tumor.[105][106][107][108]
Nivolumab is a humanIgG4 antibody that prevents T-cell inactivation by blocking the binding ofprogrammed cell death 1 ligand 1 or programmed cell death 1 ligand 2 (PD-L1 or PD-L2), a protein expressed by cancer cells, withPD-1, a protein found on the surface of activated T-cells.[109][110] Nivolumab is used in advanced melanoma, metastatic renal cell carcinoma, advanced lung cancer, advanced head and neck cancer, and Hodgkin's lymphoma.[111]
Ofatumumab is a second generation humanIgG1 antibody that binds toCD20. It is used in the treatment ofchronic lymphocytic leukemia (CLL) because the cancerous cells of CLL are usually CD20-expressing B-cells. Unlikerituximab, which binds to a large loop of the CD20 protein, ofatumumab binds to a separate, small loop. This may explain their different characteristics. Compared to rituximab, ofatumumab induces complement-dependent cytotoxicity at a lower dose with lessimmunogenicity.[112][113]
As of 2019,pembrolizumab, which blocksPD-1, programmed cell death protein 1, has been used via intravenous infusion to treat inoperable or metastaticmelanoma, metastaticnon-small cell lung cancer (NSCLC) in certain situations, as a second-line treatment forhead and neck squamous cell carcinoma (HNSCC), afterplatinum-based chemotherapy, and for the treatment of adult and pediatric patients with refractory classicHodgkin's lymphoma (cHL).[114][115] It is also indicated for certain patients withurothelial carcinoma,stomach cancer andcervical cancer.[116]
Rituximab is a chimeric monoclonal IgG1 antibody specific for CD20, developed from its parent antibodyIbritumomab. As with ibritumomab, rituximab targets CD20, making it effective in treating certain B-cell malignancies. These include aggressive and indolent lymphomas such asdiffuse large B-cell lymphoma and follicular lymphoma andleukemias such as B-cellchronic lymphocytic leukemia. Although the function of CD20 is relatively unknown, CD20 may be acalcium channel involved in B-cell activation. The antibody's mode of action is primarily through the induction of ADCC andcomplement-mediated cytotoxicity. Other mechanisms include apoptosis[clarification needed] and cellular growth arrest. Rituximab also increases the sensitivity of cancerous B-cells to chemotherapy.[117][118][119][120][121]
Trastuzumab, sold under the brand name Herceptin among others, is amonoclonal antibody used to treatbreast cancer andstomach cancer.[122][123][124][125] It is specifically used for cancer that isHER2 receptor positive.[122] It may be used by itself or together with otherchemotherapy medication.[122] Trastuzumab is given byslow injection into a vein andinjection just under the skin.[122][126]
Common side effects include fever, infection, cough, headache, trouble sleeping, and rash.[122] Other severe side effects includeheart failure,allergic reactions, andlung disease.[122] Use duringpregnancy may harm the baby.[127] Trastuzumab works by binding to theHER2 receptor and slowing down cell replication.[122]
Trastuzumab was approved for medical use in the United States in September 1998, and in the European Union in August 2000.[128][125] It is on theWorld Health Organization's List of Essential Medicines.[129]
Immune checkpoints affect the immune system function. Immune checkpoints can be stimulatory or inhibitory. Tumors can use these checkpoints to protect themselves from immune system attacks. Checkpoint therapies approved as of 2012 block inhibitory checkpoint receptors. Blockade of negative feedback signaling to immune cells thus results in an enhanced immune response against tumors.[110] As of 2020, immune checkpoint blockade therapies have varied effectiveness. InHodgkin lymphoma and natural killerT-cell lymphoma, response rates are high, at 50–60%. Response rates are quite low for breast and prostate cancers, however.[130] A major challenge are the large variations in responses to immunocheckpoint inhibitors, some patients showing spectacular clinical responses while no positive effects are seen in others. A plethora of possible reasons for the absence of efficacy in many patients have been proposed, but the biomedical community has still to begin to find consensus in this respect. For instance, a recent paper documented that infection withHelicobacter pylori would negatively influence the effects of immunocheckpoint inhibitors ingastric cancer.,[131] but this notion was quickly challenged by others.[132]
One ligand-receptor interaction under investigation is the interaction between the transmembraneprogrammed cell death 1 protein (PDCD1, PD-1; also known as CD279) and its ligand,PD-1 ligand 1 (PD-L1, CD274). PD-L1 on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T cell activities. It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack. PD-L1 on cancer cells also inhibits FAS- and interferon-dependent apoptosis, protecting cells from cytotoxic molecules produced by T cells. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor.[133]
The first checkpoint antibody approved by the FDA wasipilimumab, approved in 2011 to treat melanoma.[134] It blocks the immune checkpoint moleculeCTLA-4. As of 2012, clinical trials have also shown some benefits of anti-CTLA-4 therapy on lung cancer orpancreatic cancer, specifically in combination with other drugs.[135][136][137] In on-going trials the combination of CTLA-4 blockade with PD-1 orPD-L1 inhibitors is tested on different types of cancer.[138]
However, as of 2015 it is known that patients treated with checkpoint blockade (specifically CTLA-4 blocking antibodies), or a combination of check-point blocking antibodies, are at high risk of having immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepaticautoimmune reactions.[109] These are most likely due to the breadth of the induced T-cell activation when anti-CTLA-4 antibodies are administered by injection in the bloodstream.[citation needed]
A 2024 cohort study of ICI use during pregnancy showed no overreporting of specific adverse effects on pregnancy, fetal, and/or newborn outcomes, interestingly.[139]
Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood.[140] At the same time the levels of circulating antibodies were lower, suggesting that local administration of the anti-CTLA-4 therapy might result in fewer adverse events.[140]
Initial clinical trial results with IgG4 PD1 antibodynivolumab were published in 2010.[110] It was approved in 2014. Nivolumab is approved to treat melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, andHodgkin's lymphoma.[141] A 2016 clinical trial for non-small cell lung cancer failed to meet its primary endpoint for treatment in the first-line setting, but is FDA-approved in subsequent lines of therapy.[142]
Pembrolizumab (Keytruda) is another PD1 inhibitor that was approved by the FDA in 2014. Pembrolizumab is approved to treat melanoma and lung cancer.[141]
AntibodyBGB-A317 is a PD-1 inhibitor (designed to not bind Fc gamma receptor I) in early clinical trials.[143]
In May 2016, PD-L1 inhibitoratezolizumab[144] was approved for treating bladder cancer.
Anti-PD-L1 antibodies currently in development includeavelumab[145] anddurvalumab,[146] in addition to an inhibitory affimer.[147]
Other modes of enhancing immuno-therapy include targeting so-called intrinsic immune checkpoint blockades. Many of these intrinsic regulators include molecules withubiquitin ligase activity, includingCBLB. More recently,CISH, a molecule with ubiquitin ligase activity, was found to be induced by T cell receptor ligation (TCR) and suppressed by targeting the critical signaling intermediate PLC-gamma-1.[148] The deletion of CISH in effector T cells dramatically augments TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down CISH, resulting in a significant increase in functional avidity and sustained tumor immunity. Surprisingly no changes in activity of STAT5, CISH's purported target. Thus CISH represents a new class of T-cell intrinsic immunologic checkpoints with the potential to enhance adoptive immunotherapies.[149][148][150]
Many cancer patients do not respond to immune checkpoint blockade. Response rate may be improved by combining that with additional therapies, including those that stimulate T cell infiltration. For example, targeted therapies such as radiotherapy, vasculature targeting agents, and immunogenic chemotherapy[151] can improve immune checkpoint blockade response in animal models.
Combining immunotherapies such as PD1 and CTLA4 inhibitors can create to durable responses.[152][153]
Combinatorial ablation and immunotherapy enhances the immunostimulating response and has synergistic effects for metastatic cancer treatment.[154]
Combining checkpoint immunotherapies with pharmaceutical agents has the potential to improve response, and as of 2018 were a target of clinical investigation.[155] Immunostimulatory drugs such asCSF-1R inhibitors andTLR agonists have been effective.[156][157]
Two independent 2024 clinical trials reported that combinations ofJAK inhibitors with anti–PD-1 immunotherapy could improve efficacy. A phase 2 trial investigated the combination as a first-line therapy for metastatic non-small-cell lung cancer. Administration of itacitinib after treatment with pembrolizumab improved therapeutic response. A separate phase 1/2 trial with patients with relapsed/refractory Hodgkin's lymphoma combinedruxolitinib andnivolumab, yielding improved clinical efficacy in patients who had previously failed checkpoint blockade immunotherapy.[158]
Cytokines are proteins produced by many types of cells present within a tumor. They can modulate immune responses. The tumor often employs them to allow it to grow and reduce the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response. Two commonly used cytokines are interferons and interleukins.[159]
Interleukin-2 andinterferon-α are cytokines, proteins that regulate and coordinate the behavior of the immune system. They have the ability to enhance anti-tumor activity and thus can be used as passive cancer treatments. Interferon-α is used in the treatment ofhairy-cell leukaemia, AIDS-relatedKaposi's sarcoma,follicular lymphoma,chronic myeloid leukaemia andmelanoma. Interleukin-2 is used in the treatment ofmelanoma andrenal cell carcinoma.[160]
Interferons are produced by the immune system. They are usually involved in anti-viral response, but also have use for cancer. They fall in three groups:type I (IFNα and IFNβ),type II (IFNγ) andtype III (IFNλ). IFNα has been approved for use inhairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma,chronic myeloid leukaemia and melanoma. Type I and II IFNs have been researched extensively and although both types promote anti-tumor immune system effects, only type I IFNs have been shown to be clinically effective. IFNλ shows promise for its anti-tumor effects inanimal models.[161][162]
Unlike type I IFNs,Interferon gamma is not approved yet for the treatment of any cancer. However, improved survival was observed whenInterferon gamma was administered to patients withbladder carcinoma andmelanoma cancers. The most promising result was achieved in patients with stage 2 and 3 ofovarian carcinoma. Thein vitro study of IFN-gamma in cancer cells is more extensive and results indicate anti-proliferative activity of IFN-gamma leading to the growth inhibition or cell death, generally induced byapoptosis but sometimes byautophagy.[163]
Interleukins have an array of immune system effects.Interleukin-2 is used in the treatment ofmelanoma andrenal cell carcinoma. In normal physiology it promotes both effector T cells and T-regulatory cells, but its exact mechanism of action is unknown.[159][164]
Due to the high cost of immunotherapy and the reluctance of insurers to pre-authorize treatment, various genetic and molecular tests have been developed to predict therapeutic response. Three major biomarkers are currently FDA-approved and widely used in clinical practice: (1)programmed death-ligand 1 (PD-L1) expression, (2)microsatellite instability (MSI) ormismatch repair deficiency (dMMR), and (3)tumor mutational burden (TMB).[165][166]
PD-L1 expression, detected via immunohistochemistry, may indicate which tumors are more likely to respond to immune checkpoint inhibitors by revealing the presence of proteins that help cancer cells evade immune surveillance. However, its predictive value is limited by variability in expression across tumor types, locations, and testing platforms.[167][168][169] MSI and dMMR, identified through molecular orimmunohistochemical testing, indicate a deficiency inDNA repair mechanisms and are associated with high mutation rates that may increase tumorimmunogenicity. These biomarkers have been approved to guide the use of checkpoint inhibitors in several cancer types. TMB, measured by next-generation sequencing, quantifies the total number ofsomatic mutations in a tumor genome. High TMB has been associated with improved responses to immunotherapy, although its clinical utility remains controversial and context-dependent.[170][171] As of 2023, reliance on TMB as a selection criterion for immunotherapy was still debated in the scientific community.[172][173]
In addition to these biomarkers, the FDA has approved certain drug-companion diagnostic pairings based on genetic mutations. For example,BRAF-targeted therapies for metastaticmelanoma are only indicated for patients whose tumors harbor a BRAF mutation.[174]
While these tests are now commonly marketed as essential tools forprecision oncology, they remain costly.[175] Moreover, some have been the subject of controversy or misuse. Notable examples include theDuke University cancer fraud scandal and questionable claims surrounding so-called "liquid biopsies."[176][177][178]
Anoncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed byoncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune responses for long-term immunotherapy.[179][180][181]
The potential of viruses as anti-cancer agents was first realized in the early twentieth century, although coordinated research efforts did not begin until the 1960s. A number of viruses includingadenovirus,reovirus,measles,herpes simplex,Newcastle disease virus andvaccinia have now been clinically tested as oncolytic agents. T-Vec is the first FDA-approvedoncolytic virus for the treatment of melanoma. A number of other oncolytic viruses are in Phase II-III development.[182]
Certain compounds found inmushrooms, primarilypolysaccharides, can up-regulate the immune system and may have anti-cancer properties. For example,beta-glucans such aslentinan have been shown in laboratory studies to stimulatemacrophage,NK cells,T cells and immune systemcytokines and have been investigated in clinical trials asimmunologic adjuvants.[183]
Many tumors express mutations. These mutations potentially create new targetable antigens (neoantigens) for use in T-cell immunotherapy. The presence of CD8+ T cells in cancer lesions, as identified using RNA sequencing data, is higher in tumors with a highmutational burden. The level of transcripts associated with the cytolytic activity of natural killer cells and T cells positively correlates with mutational load in many human tumors. In non–small cell lung cancer patients treated with lambrolizumab, mutational load shows a strong correlation with clinical response. In melanoma patients treated with ipilimumab, the long-term benefit is also associated with a higher mutational load, although less significantly. The predicted MHC binding neoantigens in patients with a long-term clinical benefit were enriched for a series oftetrapeptide motifs that were not found in tumors of patients with no or minimal clinical benefit.[184] However, human neoantigens identified in other studies do not show the bias toward tetrapeptide signatures.[185] Finally, effectiveness of neoantigens may also be regulated by the specificHLA repertoire possessed by specific patient sub-groups.[55]
In the 1980s, Japan'sMinistry of Health, Labour and Welfare approvedpolysaccharide-K extracted from the mushroom,Coriolus versicolor, to stimulate the immune systems of patients undergoing chemotherapy. It is adietary supplement in the US and other jurisdictions.[186]
Small molecule drugs are also under development as cancer immunotherapeutic agents, offering potential advantages over traditional antibody-based therapies such as improved tissue penetration, oral bioavailability, and lower production costs.[187] These molecules target key immune checkpoints and signaling pathways—including PD-1/PD-L1, STING, chemokine receptors, and negative regulators of T cell function—modulating the tumor microenvironment and enhancing anti-tumor immune responses.[188][189] Notable candidates includeBMS-202 andCA-170, which disrupt PD-1/PD-L1 interactions, and compounds targeting adenosine, prostaglandin, and innate immune pathways, many of which are advancing through clinical trials.[188]
While immunotherapy has provided a tool for combating cancer, a significant clinical challenge comes with it. Cancer cells can develop resistance to immunotherapy treatment, which decreases the efficacy of the treatment. A substantial proportion of patients either begin treatment with resistance, causing failure in response, or develop resistance after the medication is administered.[190][191] A recent review estimated that a majority of patients with solid tumors eventually acquire resistance to immunotherapy.[190][191]
Resistance to immunotherapy falls under either the category of primary or innate resistance, which causes a lack of response to immunotherapy treatment from the get-go, or acquired resistance, where there is an initial positive response to treatment followed by regression.[190][191] Resistance arises through mechanisms that alter the interaction between tumor cells, the immune system, and the tumor microenvironment.
Tumor antigenicity, or the ability for the immune system to recognize cancer cells, is a primary target for resistance. Resistance mutations that down-regulate (decrease) the expression of antigen-presenting factors allow the immune system to ignore the presence of cancer cells. Themajor histocompatibility complex (MHC), which presents antigens on the cell surface to prompt immune recognition, is often a target[190]. WhenT cells can no longer identifymalignant cells, this renders therapies and immune recognition useless.
A second mechanism of immunotherapy resistance is impaired immune cell function. Cancers are found to attract and rely on immune suppressors such as regulatory T cells or other cells in the tumor microenvironment to decrease the response of immune cells.[190] Further, reducing the activity of cytotoxic T cells by sustaining expression of inhibitory receptors limits the effectiveness of immune checkpoint inhibitors.[192]
Cancers can modify the tumor microenvironment itself, creating physical and biochemical barriers to immune attack. Abnormal vasculature is a prominent way of doing this.[190] Tumors secrete factors that attract the growth of blood vessels (angiogenesis) that encourages further methods of nutrient transport, feeding the tumor. Additionally, cancer cells can produce nerve growth factor which causes healthy neurons to develop around and within tumors. This is promotes further tumor growth because nerves produce neurotransmitters 5HT that prompt tumor cell proliferation. Essentially solid tumors are able to create networks of feedback loops, hijacking healthy cells.[191]
We demonstrate here for the first time the successful conjugation of a small molecule TLR7 agonist to an antitumor mAb (the anti-hCD20 rituximab) without compromising antigen specificity.
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