See also Acetylation of Histones See also Cancer Specific Antibodies.
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 agents, thereby potentially resulting in a reduction in toxic side effects. It is also known in the art that therapeutically effective dosages of chemotherpaeutic agents can vary when these drugs are used in treatment combinations. 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).
Combination therapies are often employed in cancer treamtnet. For example, two or more accepted therapies such as ehmotherapy and radiotherapy have been employed. The therapetuci gain dervied form certain combiantion therapies can be (1) spatial cooperation–chemotehrapy and radiotherapy eradicate disase in different anatomical sites, (2) toxicity independent –kill due ot chemotherapy is added to that dervied form radiotherapy becasue of non-overlapping normal organ toxicity, (3) nromal tissue proteciton-agents that make it possible to delvier alrger doses of radiation to teh target adn (4) ehnacement of tumor response–one agen (chemotherapy or radiation) preferentally sensitizes tumor cells to the other such that the effect of the two is greater than would be epxected by adding effect of each individually. (Sgouros, US 2009/0054720)
Combination of Epigenetic Factors and Antibodies:
–HDAC Inhibitor+ Immunotherapy:
Hodge, (US 2019/0183870A1) discloses a method of reducing cancer cell growth which includes a combination of a histone deacetylase (hDAC) inhibitor and immunotherapy. The invention is predciated, at least in part, on the discovery that clinically relevant exposure of prostate and breast human carcinoma cells to histone deacetylase (HDAC) inhibitors reverses tumor immune excape to T-cell mediated lysis. Immunotherapy includes the inducing, enhancing or suppressing of an immune response. Types of immunotherapies include checkpoint inhibitors, immunomodulators, cell-based immunotherapies, mAbs, radiopharmaceuticals and vaccines. Although not wishing to be bound by any particular theory, it appears that the observed reversal of epienetic silencing promoting immune evasion is driven by a response to cellular stress through activation of the unfolded protein response (UPR). In one example carcinoma cells exposed to the HDAC inhibitor vorinostate were significantly more sensitive to CTL-mediated killing.
—-CD33 targeting compound a Epigenetic Factor: Walter (US 2016/0317657A1) disclsoes a combination epigenetic factors and bispecific compounds targeting CD33 and CD3 for the treatment of myeloid leukemia, wherein the epigenetic factor is selected form the group consiting of histone deacetylate (HDAC) inhibitors, DNA methyltransferase (DNMT) I inhibitors, hydroxyurea, Granulocyte-Coloy stimulating Factor (G-CSF), histone demethylase inhibitors and ATRA (All Trans-retinoic acid).
Cancer Treatment Strategies, Generally:
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).
Cancer treatment can include the use of chemotherpaeutic agents. For example, Suberoylanilide Hydroxamic Acid (SAHA) is a hydroxamic acid-based hybrid polar compound that inhibits histone deacetyalte (HDAC) activity and induces terminal differentiation, cell growth arrest and/or apoptosis of tumor cells in vtiro. (Sgouros, US 2009/0054720)
Radiation/Radiotherapy:
Cancer cells can be weakeend and ulimately killed by bombardment with certain kinds of radiation. Retrospective analysis of cancer radiotherapy, for example in the case of prostate cancer, have demosntrated that failure to acheive local control of the primary tumor is strongly associated with eventual metastatic dissemination of disease. (Sgouros, US 2009/0054720)
External Beam Radiation: uses a radiation source that is external to the patent, typically either a radioisotope, such as 60Co, 137Cs or a high energy x-ray sources, such as a linear accelerator.
Types of Radiopharmaceutical Agents: contain at least one radiation-emitting radioisotope. They are routinely used in nuclear medicine for the diagnsois or therapy of various diseases. The radiolabelled pharmaceutical agent, for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation sources. The term “antibody radioconjutate” (ARC) refers to a source of ionizing radiation (e.g., alpha and beta partciels, and gamma rays) linked to a targeting agent (i.e., an antibody). Actinium-2225 (Ac-225) for example is an ideal source of radiation for such purpose.
–Targeted alpha therapy (TAT): takes advantage of the cobmination of the highly potent radibiologcial properites of an alpha aprticle emitting payload and a tumor targeting moeity such as a mAb. The alpha particles are characterized by high linear energy trasnfer with a relative biological effectiveness t to 8 fold greater than the of X-rays. When coupled to a suitable targeting moeity the radiation dose can be preferentailly delviered to the surface of the tumor cell minimizing unwanted effects ont he normal surrounding tissue. The mechanisms of cytotoxicity of alpha therapy is based on the geenration of the dense ionizig track of the alpha partcile, leading to a range of DNA damages include single and double strand breaks as well as clustered DNA damage. Wickstraem (“Synergistic effect of a HER2 targeted Thorium-227 conjugate in combination with Olaparibin in a BRCA2 deficient xenograft model” Pharmaeceuticals 2019, 12, 155)
In 2013, the first in class alpha emitting radiophamracetuical Xofigo® (radium-223 dichloride) was approved by the FDA for the treamtent of castration resistant prostate cancer. Radium-223 is a calcium mimetic that selectively targets hydroxyapatite in areas of high bone turnover ushc as bone metastases, exerting a cytooxic effect on adjacent tumor cells through the induction of complex DNA double strand breaks (DSBs). Wickstraem (“Synergistic effect of a HER2 targeted Thorium-227 conjugate in combination with Olaparibin in a BRCA2 deficient xenograft model” Pharmaecuetixals 2019, 12, 155)
Combination Radiation therapies which are suitable for use in combination treatments include the use of (a) external beam radiation and (b) a radiopharmaceutical agent which includes a radiation-emitting radioisotope.
–With HDACs:
Sgouros (US 2009/0054720) discloses a method for treating cancer in a patient in need thereof comprising administering to said patient a frist amount of a histone deacetylase (HDAC) inhibitor, wherein said histine deacetylase inhibitor is suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt thereof and a second amount or radiation, wherein the first and second amounts together comprise a therapeutially effective amount.
–HDAC + Alpha Therapy:
Wickstraem (“Synergistic effect of a HER2 targeted Thorium-227 conjugate in combination with Olaparibin in a BRCA2 deficient xenograft model” Pharmacueticals 2019, 12, 155) discloses targeted thorium-227 conjugates (TTCs) that consist of the alpha particle emitter thorium 227 complexed with a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting mAb. Specifically, the efficacy of human epidermal growth factor receptor 2 (HER2)-TTC was tested in combination with the poly-ADP ribose polymarase (PARP) inhibitor (PARPi), olaparib. HER2 is a transmembrane tyrosine kinase receptor that is part of the human epidermal growth factor receptor (EGFR) family. The normal function of HER2 is to promote growth and proliferation, while in oncology overexpression of HeR2 is a clinically validated target linked to poor prognosis and treamtent outcomes in several cancer types. The in vitro combination effects were determined to be synergistic in DLD BRCA2 -/- human colorectal adenocarcinoma isogenic cell line DLD-1. The 3,2-HOPO chelator was conjugated to free amino side-chain of lysine residues on trastuzumab via amide bond formation, yielding the HER2-antibody-chelator conjugate enabling complexation of thorium 227. The in vitro combiantion effect of HER2-TTC and PARPi olaparib was evaluated on the colonrectal adenocarcinoma cell like DLD-1 parental and DLD-1 BRCA2 -/-. BRCA germline mutations accoutn for about 5-10% of breast cancers and 10-18% of ovarian cancers. Although HER2 overexpressing breast cancers apepar seldom to carry BRCA mutations, ovarian cancers have significantly higher numbers of BRCA mutant/HER2 positive cases and this patient population would thus rerpesent a potnetial clincial indicaiton for further explaration for the combination. New tumor specific antigens expressed by BRCA deficient breast cancers may also form the basis for the development of new TTCs.
–with Radiolabelled HER2-targeting Single Domain antibody:
Dewulf “Preclinical synergistic effects when comibning a radiolabelled HER2-targeting single domain antibody with PARP inhibitor Olaparib” J. Translational Medicine, 24:83 (2026) discloses that 225AC DOTA labelled sdAb specifically bound to HER2 low expressing DLD-1 BRCA2 -/- cells in vitro, inflicted DNA damage (elevated yH2AX) and decreased cell viability and that this effects was invigorated upon combination with the PARP inhibitor Olaparib.
HDACs remove acetyl groups from histones, generally promoting transcriptional repression.
Sgouros, (US 2009/0054720) discloses that HDAC inhibitors, such as SAHA can be used in combination with a radiation sources such as external beam irradiation or a radioisotope, such as a radiopharmaceutical, to provide therapeutically effective anticancer effects. An unexpected synergistic interaction between the HDAC inhibitor and the radiation source results in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect resulting from administration of the two treatments each at a therapeutical dose. These observations suggest that HDAC inhibitors, such as SAHA, can act as radiosensitizers that can be used in combination with radiotherapy for the treatment of cancer.
–Short chain fatty acids (SFAs): Typically, HDAC inhibitors fall into 5 general classes; (A) hydroxamic acid derivative; (b) cyclic tetrapeptides; (c) short chain fatty acids (SCFAs); (d) benzmide derivatives and (e) electrophilic ketone derivatives. (Sgouros, US 2009/0054720)
See also Combination HCAC inhibitors with radiopharmaceuticals (above)
Electroporation:
Novocure has developed FDA approved Optune Pax, which is a portable device that delivers alternating electric fields, known as tumor treating fields (TTField) to the abdomen for the treatment of adult patients with locally advanced pancreatic cancer. The therapy is adminsitered through electrically insulated adhesive patches taht are placed on teh apteint’s skin and connected to an electrid field generator.
Targeted Freezing:
SYNC-T therapy involves lyzing a portion of the tumor using targeted freezing, multi-targeted immune activation with the TME with SV-102 and regional lymph nodes leading to T cell activation. The SV-102 is a fixed dose, multi-target biologic that includes an anti-PD-1 mAb (blocking PD1 allows T cells to effectively kill target cancer cells), an anti-CTLA-4 mAb (enhances anti-tumor responses by blocking CTLA4, allowing CD28 to bind CD80/CD86 to stimulate T cell priming and also by downregulating Treg suppression), a CD40 agonistic mAb (activates APCs) and and TLR9 agonist (stimulates plasmacytoid DCs and enhances Th1 medaited anti-tumor responses and stimulates SPCs in the tumor draining lymph nodes). The oncolysis is perforemd via targeted freezing which is acheived using the ICESPHERE Cryoablation needles to geenrate about a 10 mm ice ball, followed by passive thawing.
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 therapeutic 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 responces. (Brissette “Identificaiton of cancer targets and therapeutics using phage display” Current Opinion in Drug Discovery and Development 2006, 9(3) 363-369).
Another method used by NEC Bio is to start (1) with DNA and RNA sequencing of tumor and blood samples, (2) using AI driven NEC Immune Profiler platform to select and rank the top 15 neoantigens present in the tumor, (3) incorporate these neoantigens into a DNA paslmid which is then (4) used to transform the Salmonella enteric Typhi strain Ty21a bacteria which has been used for decades in a live, oral typhoid vaccine and is known to be highly effective in delivering its payload to the small intestin.
(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: involves the transfer of autologous antigen-specific T cell generated ex vivo. The T cells sued can be generated wither by expansion of antigen specific T cells or redirection of T cells through genetic engineering. Transfer of viral antigen specific T cells is well established procedure used for the treamtent of transplant associated viral infections and rare iral related malignancies.
(CD4+ or CD8+ cells): Adoptive immunotherpy 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).
Novel specifities in T cells have been successfully generated through the genetic transfer of transgenic T cell receptors or chimeric antigen receptros (CARS): CARs are synthetic receptors consisting of a targeting moiety that is assocaited with one or mroe signaling domains in a single fusion molecule. In general, the binding moiety of a CAR consists of an antigen-binding domain of a single-chain antibody (scFv), comprising the light and variable fragments of a mAb joined by a flexible linker. Biending moeities based on receptor or lignd domains ahve also been sued successful. The signaling doamins for first gerneation CARs are derived form teh cytoplasmic region of the CD3zeta or the Fc receptor gamma chains. First generation CARs have been shown to successfully redirect T cell cytooxicity. However, they failed to provide prolonged expansion and anti-tumor activity in vivo. Signlaing domains from a co-stimualtory molecules, as well as trasnmembrane and hinge domains ahve been added to form CARs of second and thir generations, leaind to some successful therapetuic trails in humans, where T cells could be redirected against cells expressing CD19.
Tumor infiltrating lymphocytes (TILs) are a grouping of mostly T cells that enter tumors and elicit an immune response. 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 demonstrated 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 approaches. 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).
There are two broad forms of TIL therapy. First, there is the traditional approach that does not require engineering. A second emerging TIL therapy involves genetic engineering. This may require CRISPR. For example, researchers have used CRISPR/Cas9 gene editing to modify tumor infiltrating lymphocytes (TILs) (See NCT04426669). By deactivating the CISH gene, modified TILs were better able to recognize and attack cancer cells. CISH encodes cytokine inducible SH2 containing protein, a novel intracellular immune checkpoint target and a founding member of the SOCS family of E3-ligases, using tumor infiltrating lymphocytes (TILs) genetically edited with CRISPR Cas9 in patient with metastatic gastrointestinal epithelial cancers. CISH is believed to be a key factor preventing T cells from recognizing and eliminating tumors. With the gene editing approach, the checkpoint inhibition is accomplished and permanently hardwired into the T cells.
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 intracellular signaling domains capable of eliciting a T cell response. CARs that contain only the CD3-epsilon endodomain are known as first generation CARS. those that contain one costimulatory 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 success has been amassed with CAR T cells targeting CD19, a surface protein involved in B cell signalaing 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 sucdess 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 therapy 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. (Novik, US 2017/0360836).
Some patients given CAR T cell therapy and other immune therapies exxperience a dangerous and soemtimes life threatening side effect called cytokine release syndrome in which the infused, activated T cells produce a systemic inflammatory resposne in which there is a rapid and massive release of cytokines into the bloodstream. Cytokine storms are also a problem after other infectious and non-infectious sitmuli.
–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:
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.
Androgen deprivation therapy (ADT): refers to a treatment for cancer in which the level of androgen hormones, such as testosterone, in a patient are reduced, typically by phamraceutical or surgical methods. Hodge, US 2019/0183870A1)
Counteracting Angiogenesis:
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 clinically 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.
Nanoradioenhancer: Nanobiotix uses a nanoradioenhacer that includes a suspension of crystalline, inorganic nanopartciles that are directly injected into solid tumors. When activated by radiation, the nanoradioenhancer absorbes and releases energy that destroys the tumor from whin, wihout increasing damage to surrounding healthy tissue.
Gold Nanorods: Sona Nanotech is devloping gold nanords which are inert, notoxic and uniquely biocompatible. They are injected into a solid cancer tumor, then the tumor is exposed to near infrared light, alloiwng non-thermal light energy to harmless penetrate about 2.5 cm of tissue. When tuned to the matching wavelenght, the leight energy casues the nanorods to resonate, which converts the non-thermal energy into heat.
Localized Drug Delivery:
RenovRx uses a catheter (or small plastic tube) which is inserted inot the leg via a small inscision and delivered to an aertery adacent to a thumor to deliever a full doese of chemotherapy at the tumor site. Instead of flooding the whole body with chemotherpay, it is delivered locally.
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.
Targeting the Tumor Microenviroment:
Existing oncology therapetuics are either so specific they can target only part of a tumor or so generlaized they kill healthy tissue. Seekyo Therapeutics seeks instead to target only teh functional proteins that are always present in all solid tumors. In solid tumors, there are many kinds of different canerous cells. The company developed a method that eocnompasses the funcitonal proteins present in the tumor microenviornment (TME) to destroy all the different cancer cells inside the same tumor. The company’s lead compound, SKY01, links to albumin in the patient’s blood stream and becomes a macromolecule. It uses the pharmacokinetics of albumin, which the tumor sees as a nutritional source, to draw the macromolecule to the tmor, and the beta glucuronidase within the TME to release monomethl auristain E, a cytotoxic paylod that induces apoptosis. Thus, the therapy does not need to get inside the cell to be active it just needs to be inside the TME.
Genetically engineered/oncolytic viruses:
Tudrique: is a genetically modified oncoyltic viral therapy for the treatment of advanced, refractory melanoma It is indicated in combination with nivolumab for the treatment of adult patietns with unresectable advanced cutaneous melanoma who experience disease progression with a pgroammed death receptor-1 (PD-1 blocking antibody) based regimen.
Tudriqev (vusolimogene oderparepvec-wtpg, also called RP1) is an engineered oncolytic herpes simplex virus type 1 (HSV-1). The clever part is that it attacks melanoma in two complementary ways: directly destroying tumor cells and stimulating an antitumor immune response. two viral genes are deleted (ICP34.5/ICP47), while two functional transgenes are added (GALV-GP-R− and GM-CSF).
The engineered HSV-1 preferentially replicates within tumor cells. Its ICP34.5 genes are deleted, which attenuates the virus and contributes to tumor-selective replication. Removing genes such as ICP34.5 cripples replication in healthy cells while many tumor cells—with defective antiviral defenses—remain permissive.
The ICP47 gene is also deleted. RP1 has been engineered to express GALV-GP-R−, a fusogenic glycoprotein derived from gibbon ape leukemia virus. It promotes cell-cell fusion, increasing tumor-cell killing and making that death particularly immunogenic.
When infected melanoma cells lyse, they release tumor-associated antigens. Those antigens can then be recognized by the patient’s immune system. The virus carries a gene encoding human GM-CSF, which helps stimulate/recruit immune cells and enhances the immune response against those released tumor antigens.
Cell Checkpoint Inhbitors: See also cancer specific antibodies
Tudriqev is used with the PD-1 checkpoint inhibitor nivolumab. Conceptually, RP1 helps make the tumor more immunogenic and generates an antitumor immune response, while PD-1 blockade helps prevent the tumor from shutting that T-cell response down.
Tudriqev is injected directly into the tumor, so the initial viral concentration is overwhelmingly at the tumor site rather than throughout normal tissues.
DNA Damage Response Inhibitors:
DNA damage can be due to endogenous factors, such as spontaneous or enzymatic reactions, ehcmical reacitons, or errors in replication or may be due to exogenous factors, such as UV or ionizing radiation or genotoxic chamicls. The repair pathways that overcome this damage are collectively referred to as the DNA damage response or DDR. This signaling network acts to detect and orchestrate a cell’s reponse to certain forms of DNA damage, most notably double strand breaks and replication stress.
Within the DDR, there are several DNA repair mechanisms, including base exision repair, nucleotide excision repair, mismatch repair, homology recombinant repair, and non-homologous end joining. About 450 human DDR genes code for prtoeins with roles in physiological processes. Dyregualtion of DDR leads to a variety of disorders, including genetic, neurodegenerative, immune, cardiovascular and metab olic diseaes and cancers. For example,t he geens OGG1 and XRCC1 are part of the base excision repair mechanism of DDR, and mutations in these genes are found in renal, breast, and lung cancers, while the genes BRCA1 and BRCA1 are invovled in homologous repair mechanisms and mtuations in these genes elads to an increased risk of breast, voarian, prostate, pancreatic, as well as gastrointestinal and hematological cancers.
PARP Inhbitors: have been approved for use in breast and ovarian cancer, particularly in patients having BRCA1/2 mutatations. To date the FDA has approved alparib, niraparib, rucaparib and talazoparib as monotherapy agents, specifically in patients with germline and somatic mutations in the BRCA1 and BRCA2 genes. These PARP inhibitors all bind to the binding site on the cofactor, b nicotinamide adenine dinucleotide (b-NAD+), in the catalytic domain of PARP1 and PARP2. However, they differ in their capability to trap PARP1 on DNA, which such capability seems to correlate with cytotoxicity and drug efficacy.
Mutations in BRCA genes and others in the HR system are not prevalent in many cancer types. So, to better harness the therapeutic benefits of PARP inhibitors in such cancers, one can induce artificial synthetic lethality by parking a PARP inhibibitor with either chemotherapy or radiation therapy. Various PARPi combiantion therapy clinical trials are ongoing. Many invovle combinations with ehmotherpaies. Radiation therapy which uses inizing radiation liek alpha and beta particles, X-rays and gamma rays, may have an advantage over chemotherapy in terms of toxicity.
Mechanisms proposed for combinatorial PARP inhibitor therapies include (1) increased accumualtion of DNA damage and subsequent dependence on PARP mediated DNA damage repair, (2) increased levels of trapped PARP-DNA complexes, and (3) induciton of BRCAness phenotype to elicit PARPi-BRCAness synthetic lethality.
Interference with activity/signaling between CD47 and SIRPalpha:
Anthercancer therapy is a targeting agent that intefers with or reduces the activity and/or signaling between CD47 (e.g., on a target cell) and SIRPalpha (e.g., on a phagocytic cell) through interaction with either CD47 or SIRPalpha. A CD47 blockage refers to any agent that reduces the binding of CD47 (on a target cell) to SIRPalpha (e.g., on a phagocytic cell) or otherwise blocks or downregualtes the “don’t eat me” signal of the CD47-SIRPalpha pathway.
Treatment of Cancer Side Effects:
Gastrointestinal (GI) toxicity: is a common and potentially severe side effect of antiproliferative ancer therapies that often reuqires dose reduction or treatment interruption. It frequently manifests as diarhea and can affect between 50-80% of pateints, depending on the treatment regimen. intestinal toxicity associated with antiproliferative cancer treatments is characterized by epithelial ulceration and mucosal inflammation which resutls from the disruption of proliferative and stem cells located in teh itnestinal crypts.
There is a need for strategies to enalbe early prediction of GI toxicity druing the preclinical development of cancer treatment. (Pin, “Intestinal Organoid-based mathetmatical mdoeling predicts clinical gastrointestinal toxicity of oral oncology drugs” has developed a Aunatiative toxicology Systems (GST) modeling approach that describes drug effects in crypt proliferative cells based on measured cytotoxicity in vitro human small intestinal organoids (hSIOs), whih recapitulate the structure and cellular composition of human intestinal crypts.
Neutropenia:
—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.