Treatment of cancer
Unpredictability in Cancer Treatment
Non-correlation between In Vitro and In Vivo treatment: Cancer treatment is highly unpredictable. For example, even though the EGFR was identified in some cancers as a drug target, the in vitro effectiveness of a drug in inhibiting the EGFR turned out to be a poor proxy for how effective that drug actually was in treating cancer in vivo. Numerous EGFT inhibitors that showed promising in vitro activity failed for a variety of reasons. These included poor pharmacokinetics due to poor adsorption or rapid metabolism (or both), undersirable drug-drug ineractions, drug toxicity due to drug binding onto healthy cells, sdrug toxicity due to binding onto other receptors and metabolite toxicity. OSI Pharmaceuticals v. Apotex (USPTO, No: IPR2106-01284)
Challenges with Experimental Models: Despite some successes, many cancer still have a high mortality rate and no effective treatment. For many cancers, survival rates have not changed in decades – pancreatic cancer remains almost 100% lethal, and the oeverall survival rate for lung cancer has improved only from 13 to 16 %. The key difficulty is that cancer is a complex and heterogenous disease: many genes are amplified, deleted, mutated, and up- or down-regualted. Many pathways are activated or suppressed. These chances vary substantially in different cancers, in different patients with the same cancer, and even in different tumor samples from the same patient (Fortney, 2011, p. 465, last ¶). Although mice are crucial for cancer research, cancer is a complex, three-dimensional disease that changes, evolves and spreads through the body. Mice, easy to breed and genetically manipulate, and with a completed genome sequence, are the obvious choice for scientists who wanted to pick apart these processes and test new drugs. Bust despite having broad similarities, mice have significant differences. For one, most mouse trmours originate in different types of tissues from humans and unlike humans, their lethalaly cells can maintain the ends of their chromosomes, a key factor influencing which mutations tumour cells develop. One of the key mouse models, involves grafting human cancer cells into mice and seeing how the resulting tumours respond to treatment. But human cells are likely to behave differently in a mouse than in a human body, making results hard to interpret (Carina Dennis, Nature, (2006), pp. 739-741)
Combination Therapy and Dosing
It is recognized in the art that a benefit of using chemotherpaeutic agents in conjunction with other therpaies, e.g., an antibody antagonist, can be useful for allowing adminsitraiton of lower dooses of chemotherpaeutic agetns, thereby potentially resulting in a reduction in toxic side effects. It is also known in the art that therpaeutically effective dosages of chemotherpaeutic agents can vary when these drugs are used in treatment combiantions. Methods for experimetnally determining therapeutically effective dosages of chemotherapeutic drugs and other agents for use in combination treatment regimends are descried in the literature. For example, the use of metronomic cheotherapy dosing, i.e., providing more frequent lower doses in order to minimize toxic side effects, has been described extensively in the literature. A combiantion treatment regimen encompases treatment regimens in which administration of a chemothreapetuic agent is initiated prior to, during, or after treatment with the second agent, e.g., an antibody, and continues until any time duringtreatment with the other agent or after termination of treatment with the other agent. It It also includes treatment in which the agents being used in combiantnion are adminsitered simultaenoeusly or at differnt times and/or at decreasing or increasing intervals during the treatment period. (Van Epps (US 2007/0048325).
Cancer Treatment Strategies
Surgical debulking: If surgical removal is possible, this is a favored treatment strategy. However, surgery may miss micrometastases.
Chemotherapy: Most, if not all, chemotherapeutic agents kill cancer cells through the induction fo apoptosis. Cisplatin, for example, is extensively used for the treatment of a broad spectrum of turmors. Chemotherapy suffers from problems like drug toxicity and drug resistance (due to increased drug metabolism, increased DNA repair mechanisms and decreased drug import into cells). It also has devastating side effects such as gut-tering vomitus and diarrhea, alopecia, and fatal vulnerability to infections. Cisplatin, for example, has preogressive, irreversible side effects including nephrotoxicity and ototoxicity. Evidence indicates that cisplatin ototoxicity is closely related to the increased production of reactive oxygen species (ROS).
Tumor Immunology: Tumor cell destruction should be possible by the immune system. Strategies along this line of thought include the following:
(i) Cancer Vaccines refers to therapeutic immunization in patients with cancer, with the main aim of breaking tolerance toward self-tumor-associated antigens. One strategy is to pulse antigen presenting cells such as dendritic cells (CDs) with tumor antigens in the hope that that such DCs will induce host protective and therapeutic antitumor immunity. These approaches are currently limited for clinical application because few human tumor antigens on a tumor cell that can activate the immune system have been found. In the best studied human melanoma where a class of tumor associated proteins have been identified, it is unclear which of the identified tumor associated Ags is the best choice to induce effective tumor rejection in vivo or how effective they are.
The advent of massively parallel sequences has now made it possible to sequence the entire gehome of exome (coding regions) of tumor and matched normal cells to identify all of the muations that have occurred. The subset of those mutations that alters protein coding sequences creates personal, novel antigen “neoantigen” which may provide the “foreign” signal needed for cancer immunotherpaty This is important because the use of self antigens which are selectively expressed or overexpressed in tumors requires overcoing both central tolerance (whereby autoreactive T cells are deleted in the thymus during development) and periopheral tolerance (whereby mature T cells are suppressed by regulatory mechnisms). (Hacohen, “Getting Persoanl with Neoantigen-based therpaeutic cancer vaccines” DOI: 10 (2013).
Another interesting therapeutic approach is the use of peptides as vaccines. Phage-display libraries are panned against therapwutic antibodies. Peptides identified that resemble the original antigen to which the antibody binds have been called “mimotopes”. The resulting mimotpe may be used to elicit humoral and cellular respones. (Brissette “Identificaiton of cancer targets and therapeutics using phage display” Current Opinion in Drug Discovery and Development 2006, 9(3) 363-369).
(ii) Introduce genes encoding MHC Ags, toll-like receptor agonists, costimulatory molecules or cytokines into tumor cells. The goal here again is to improve the immunogenicity and the Ag-presenting capability of tumor cells. For example, DCs can be raised from bone-marrow stem cells upon culture with cytokine combinations. During the differentiation culture they can be transfected with recombinant viral vectors encoding cytokines like IL-12, IL-7, or IL-2. If such cells are then injected intratumorally they capture antigen, migrate to draining lymph nodes and orchestrate a potent CTL response. Artificial expression of the transgene greatly enhances the antitumor immune response.
Interestingly, most of the pulsing has been done with peptides rather then proteins (which would require DCs to process the antigen). This is because when take DCs and put them into plastic culture dishes, giving them cytokines, etc., this matures them. So most of the DCs become mature. One way to counteract this is to do this in vivo. For example, FLT3L is a way to increase DCs in vivo to increase DCs prior to taking out the blood to grow the DCs in culture. Morese et al, JCO, 2001 found that if they systemically gaive Flt3 ligand to mice, DC population increased. Then use IL-14, GM-CSF and TNFa for growing the DCs (CD34+ HPC) in vitro.
Patients given subcutaneous GM-CSF administration increase mobilization of CD80+ DCs. Studies have shown that just giving GM-CSF is therapeutic. Newer treatments include taking tumor cells from patients, growing them, transfecting them with plasmid encoding with GMCF, then irradiating them to use them as a vacine. Trials have shown this stimulated DCs leading to increased CD8+ cells at tumor sites.
Another approach is to use TLR agonists to activate local immune response. For example, the TLR7 agonist, imidazoquinolines and TLR 9 CpG are being used to activate the innate immune system.
(iii) Direct Tumor Transfection with Co-stimulatory Molecules: Another strategy is to take the tumor and turn it into an APC. Take tumor and put in rv-B7.1 to induce T cell activation and induce tumor recognition. Researchers have found that by doing this they were able to generate gp100- and MARt-1-specific T cells found in most A2+ patients.
(iv) Adoptive immunotherapy: (CD4+ or CD8+ cells): Adoptive immunotherpay of cancer refers to a therapeutic approach in which immune cells with an anti-tumor reactivity are adminstered to a tumor bearing host, with the aim that the cells mediate, either directly or indirectly, the regression of an established tumor. Transfusion of lymphocytes, particularly T lymphocytes, falls into this category and investigators at the National Cancer Institute (NCI) have used autologous reinfusion of peripheral blood lymphocytes or tumor infiltrating lymphocytes (TIL) T cell cultures from biopsies of subcutaenous lymph nodules, to treat several human cancers (US 4,690,914). For example, T cells that have a natural or genetically engineered reactivity to a patients’ cancer are expanded in vitro using a variety of means and then adoptively transferred into the cancer patient.One approach with respect to T helper cells is to adoptively transfer T helper cells to initiate CTL immunity. Infusion of CD4+ T cell clones specific for P815AB has shown tumor destruction through a CD8 mediated destruction. Other reports have shown that such transferring induces a broad immune response. For example, TIL expanded in vitro in the presence of IL-2 have been adoptively transferred to cancer patients, resulting in tumor regression in select patients with metastatic meloma. Melanoma TIL grown in IL2 have been identified as activated T lymphocytes CD3+ HLA DR+, which are predominantly CD8+ cells with unique in vitro antitumor properties. Many long term melanoma TIL cultures lyse autologous tumors in a specific MHC class 1 and T cell antigen receptor dependent manner.
It has been deomonstrated that CD8+ cytotoxic T lymphocytes (CRLs) recognize epitope peptides derived from tumor-associated antigens (TAAs) presented on MHC class I molecules and lyse tumor cells. Since the discovery of the MAGE family as the first example of TAAs, many other TAAs have been discovered using immunological apporaches. Some of the discovered TAAs are now in clinical development as targets of immunotherapy. TAAs discovered so far include MAGE, gp100, SART, and NY-ESO-1. For a listing of human tumor antigens recognized by T cells see (Cancer Immunol Immunother (2001) 50:3-15).
Chimeric antigen receptor T-cell (CAR-T) therapies:
CAR T cells combine the specificity of a mAb with the cytolytic capacity of a CAR T cell. This is achieved by fusing the scFv of a mAb (or another antigen recognition domain) to a transmembrane domain and intravellular signaling domains capable of elicity a T cell response. CARs that contain only the CD3-epsilon endodomain are known as first generation CARS. those that contan one costimulatry domain (such as CD28 or 41BB) are known as second-generation CARS; and those that contain two or more costimulatory domains are known as third generation CARS. To date, most clinical experience and sucess has been amassed with CAR T cells targeting CD19, a surface protein involved in B cell signlaing that is expressed on B cell malignancies. Given that its expression is restricted to the B cell lineage, and patients can live without healthy B cells, CD19 has emerged as a promising target for CAR T cell immunotherapy. Other targets that have demonstrated clinical sucess in B cell malignancies include CD22 fo B-ALL and BCMA for multiple myeloma. T date, most CAR T cell trials have used autologous T cells for transduction. A cancer patient’s T cells are collected, activated with antibodies or antibody coated beads, and then transduced, most commonly with a lentivirus or retrovirus, to express the CAR molecule. CAR T cells are then expanded in vitro to sufficient numbers to infuse back into the pateint. Patiens often recieve lympho depleting chemotherapy before T cell infusion. Majzner (“clinical lessons learned from teh first leg of the CAR T cell journey, Nature Medicine, 25, pp. 1341-1355, 2019)
Numerous factors can affect the potency and quality of a CART-T therpay including the production process (e.g., CD4/CD8 T cell ratios, T cell phenotype, levels of non-transduced cells, duration of activation, transgene construct (high or low epression, insolators, etc), vector choic (retroviral, adenoviral or transposon), CAR design (e.g., scFv affinity, stability and immunogenicity, spacer lenght and signaling domains) and input donar blood cells (e.g., starting cell number and exposure to different treatments and conditioning regimens). (Nature Biotechnology, 35(10), October 2017.
–Kymriah: which is developed by Novartis was approved by the FDA for treating relapsed B cell acute lymphoblastic leukemia in 25 and under.
–Yescarta, made by Kite Pharma, a Gilead Science company for example has been approved for treatment of certain types of non-Hodgkin lymphomoa in which patient’s white blood cells are extracted, modified, and then injected back into the patient. It was shown to cure 36% of patients completely and to reduce tumors in 82% of patients. It costs about $373,000.
Cancer Specific Antibodies: See outline
T Cell Activation with Treg Depletion: Knutson et al. 2005. Treg cells are known to express CTLA-4. Prudhomme G, J Luekocyte Biol, 2004 have given mice anti-CTLA4 and vacine against gp100. However, side effect get large autoimmunity.
Induce apoptosis.
–TNF, FasL and TRAIL:
In models utilizing animals engrafted with human tumors, treatment with TRAIL/Apo2L induces significant tumor-specific apoptosis, tumor regression, and improved survival with no identifiable toxicity. TNF, LT-alpha1Beta2, FasL, and TRAIL are all expressed and used to kill cancer cells by professioanl cytotoxic cells, such as CD8+ CTLs and NK cells. In addition, Fasl, TNF, and TRAIL are expressed by activated CD4+ T cells, B cells and macrophages. Human immature DCs also express these TNF family ligands on their cell membrane. Cell surface expression and secretion of these cytotoxic ligands appears to be tightly regulated and differentiation stage-dependent with the dendritic cell lineage. The possible regualtory mechanism might include activiteis of cytokines and/or metalloproteases.
Complement factor or receptor antagonists: Goldenberg (US2006/0140936) discloses multispecific antagonists that react specifically with at least one complement factor or complement regulatory protein in the thearapy of various inflammatory diseases including cancer. In preferred embodiments, the complement factor includes C3, C5, C3a, C3b and C5a.
Medof (US12/920293) disclose that administration of a C3aR antagonist and a C5aR antagonist such as an an antibody to C3aR and an antibody to C5aR induced apoptosis in a cancer cell expressing a c3a recetpor (C3aR) and a C5a receptor (C5aR). Lambris (US2011/0044983A1) also discloses treating cancer by admistering complement inhibitors such as inhibiotrs of C3aR and C3aR.
Corticosteroids: are used in the treatment of patients with blood disorders such as multiple myeloma. corticosteroids may work by causing programmed cell death of certain cells. Corticosteroids are also used in the treatment of cancer because they decrease inflammation. This cn decrease swelling around tumors in the spine and brain.
Induce phagocytosis. Cells undergoing apoptosis express specific signals, including lipids like phosphatidylserine (PS) that facilitate recognition and ingestion by macrophages. The possibility exists that one might be able to stimulate phagocytosis of tumor cells in the absence of a death signal to thereby delete cancer cells without even having any associated bystander effects observed during conventional chemotherapeutic treatment which is based on the induction of apoptosis.
Attract DCs to tumors with Chemokine: For example, injection of the chemokine CCL20 attracts DCs into the tumor, leading to induction of anti-tumor response. Intratumoral CpG can also activate tumor DC, leading to induciton of systemic anti-tumor immunity.
Counteracting Angioenesis: Counteracting angioenesis hampers tumor growth and spread. Angiogenesis involved the action of endogenous growth hormones such as vascular endotherlial growth factor (VEGF-A/B, VEGF-C and/or VEGF-D). Thus, counteracting the action of such growth factor indirectly counteracts tumor growth because angiogenesis is at least in part prevented. Placental growth factor (PIGF) is also involved in angiogenesis. Whereas PIGF is primarily involved in angiogenesis in tumour tissue, VEGF plays an important role in angiogenesis in toehr (non-tumour) tissue as well.
Tumour laser thermotherapy: has been shown to be superior to surgical exicsion, partly due to the laser induced immunological effect such as increased number of tumour infiltrating macrophages and CD8 lymphocytes (Ivarsson, British J. of Cancer, 2005, 93, 435-440).
–Photodynamic therapy (PDT): is a systemic administration of tumor localizing photosensitzers and subsequent irradiation with light of the appropriate wavelenght. The combination of drug uptake in maliganant tissues and selective delivery of laser generated light provides effective therapy, with efficient tumor cytotoxicity and minimal normal tissue damage. Activated photosensitivers interact with molecular oxygen to produce singlet oxygen that destroys neoplastic cells with minimal normal tissue dage. PDT utilizing the hematoporphyrin derviative (Hpd) has been used clincially for palliation of obstructive lesions of the esophagus, and the tracheobronchial tree, for treatment of bladder tumors and for loca control of various tumors on the skin surface (Canti, Anti-Cancer Drugs 1994, 5, 443-447). Photodynamic therapy is a chemotherapeutic approach that utilizes a bifunctional reagent that localizes to the target tissue relative to the surrounding tissue and is toxic to the arget tissue when epxosed to light.
Inhibition of Detrimental Cytokines: It is now accepted that inflammation is a driving force behind cancer and reflects that the inflammation is a protective attempt to remove the injury. However, disease progressio in cancer is dependent on the coplex interaction beween the tumor and the host inflammatory response. There is substantial evidence in advanced cancer that host factors such as weight loss, poor performance status and the host systemic inflammatory response are linked. For example, elevated level of C-reactive protein is now included in the definition of “cachexia” as a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The inflammatory cytokines that have been involed in wasting diseases are IL-6, TNF-alpha, IL-1beta and interferon-gamma (Argiles, European J Pharmacology 668, 2011, S81-S86. IL-6 psotive staining in carcinoma of the esophagus and also been assocaited with shorter survival (Chen, Mol Cancer, 2013, 12:26).
Immunotoxins: In this treatment an anti-tumor cell antibody is used to delvier a toxin to the tumor cells. However, in common with chemotherpaeutic approaches, immunotoxin therapy also suffers from drawbacks when applied to solid tumors. Tumor mass is generally impermeable in macromolecular agents such as antibodeis and immunotoxins. (Thorpe (US 2006/0228299)
Vasculature targetting: A promosing treatment strategy is to target the vasculature of solid tumors. Targeting the blood vessels of the tumors, rather than the tumor cells themselves, has certain advantages in that it is not likely to lead to the development of resistant tumor cells, and the targeted cells are readily accessible. Thorpe (US 2006/0228299)
Thorpe (US 2006/0228299) discloses that phosphatidylerine (PS) is a specific marker of tumor vasculature which has led to the development of new anti-PS immunoconjugates for delivering anti-cellular agents, toxins and coagulation factors to tumor blood vessels. Other examplary phosphatidylservine binding prtoeins includes annexins such as annexin V.
Precision Cancer Treatment:
Researchers can now sequence a person’s entire genome in mere days. Doing such sequencing can often point treatment i the right direction becasue they can reveal genetic mutations in genes that may be important in the type of cancer. Knowing the specific type of cancer can lead to personalized treatment for this type of cancer.
Treatment of Cancer Side Effects:
Pegfilgrastim-apgf injection is used to treat neutropenia (low white blood cells) that is caused by cancer medicines. It is a synthetic (man-made) form of a substance that is naturally produced in your body called a colony stimulating factor. Pegfilgrastim-apgf helps the bone marrow to make new white blood cells. This medication is usually given at least 24 hours after chemotherapy to stimulate the growth of new, healthy, white blood cells (WBC). Pegfilgrastim is a longer acting form of filgrastim and the manufacturer recommends that it should not be given within 14 days prior to chemotherapy.