Although there are more than 200 different types of cancer, four of them –breast, lung, colorectal and prostate — acount for over half of all new cases.
Acute Myeloid Leukemia:
Treatments:
–Antibody/drug conjugates:
MYLTARG (cemtuzumab ozogamicin) is a commercially avaialbe antibody/drug conjguate which is approved for teh treatment of acute myeloid leukemia in elderly patients. ((Boghaert, WO 2006/031653).
Breast Cancer see outline
Cervix Cancer: See outline
Chronic myeloid (myelogenous, myelocytic, granulocytic) leukemia (“CML”):
CML is a cancer of the blood and bone marrow characterized by overproduction of white blood cells. CML accounts for 7-20% of all luekemias adn affects an estimated 1-2/100,000 persons in the general population. CML is caused by a specific cytogenetic abnormality, the Philadelphia chromosome, which results in a clonal myeloproliferative disorder of pluripotent hematopietic stem cells. Current treatment options in the chronic phage of CML include buslfan, hydroxyurea, interfron based regimens, specific kinase inhibitor for bcr/abl or bone marrow/stem cell transplatnation (US 2006/0079458).
Colorectal cancer (CRC) (“colon cancer”): See outline
Digestive System Cancers:
Digestive system cancers including pancreatic cancer and stomach cancer, often are silent, and are not detected until they have reached a relatively advanced stage. As cuh, digestive tract cancers are associated with substantial morbidity and mortality. When detected at an early enough state, they can be treated by surgery, radiation therapy, chemotherapy or a combined modality therapy such as surgery to debulk the tumor, followed by chemotherapy to kill remaining tumor cells, including any metastatic disease.
Esophageal cancer (ECA): is the ninth most common malignancy in the world. Even when localized the 5 year survival rate is less than 20%. The most common approach to pateints with localized carcinoma of the esophagus is preoperative chemotradiotherapy.
Gastric cancer: is the second leading cause of cancer-related deaths worldwide and early detection is the key in its management. Endoscopy is widely used for screening, but the method is invasive. One patent describes a process of detecting gastric cancer by determing an expression lvel of inter-alpha trypsin inhibitor heavy chain H3 (ITIH3) (US 2012/0028269).
Pancreatic cancer: is the most fequent adenocarcinoma and has the wrost progrnosis of all cancers, with a five year survival rate. Pancreatic cancer occurs with afrequency of about 9 patients per 100k individuals making it the 11th most common cancer in the US. Currently the only curative treatment is surgery, but only 10-20% of patients are candidates for surgery at the time of presentation and of this goup, only 20% of patients who undergo a curative oepration are alive after five years. Lubman (WO2007/112082).
Glioblastoma:
Glioblastoma is the most common form of brain cancer. There are about 10,000 new cases in the U.S. each year. A very aggressive cancer gene is responsible for about a third of all glioblastomas. However, a new vaccine (EGFRvIII) has been shown to be able to educate the immune system to produce antibodies against the tumor.
Leukemia: see outline
Lung Cancer: see outline
Multiple Myeloma:
Multiple Myeloma is a malignancy of plasma cells. Neoplastic cells are located in the bone marrow, and osteolytic bone lesions are characteristic. Bone pain related to multiple lytic lesions is the mos common clinical presentation.
Multile myeloma is treated with chemotrherapeutic agents that are often initially effective, only for the blood malignance to retun months or years later. Accordingly, many patients go through 4-or more rounds of potent drug treatment to reduce the mounting myeloma cells.
An antigen, called MB281 or Protein M, is known to non-specifically bind to immunoglobulins with high affinity. MG281 protein has the properties of a B-cell super antigens in that immunoglobulin reactivity with this protein is non-specific. The protein is about 556 amino acids long and contains a 16-36 amino acid transmembrane domain.
treatment:
Anti-CD38: DARZOLEX (Johnson & Johnson) is an anti-CD38 antibody that kills multiple myeloma cells by attaching to CD38 which is present at greater amounts on myeloma cells.
Myelodysplastic Syndromes (MDS):
MDS are a hterogeneous group of clonal hematologic disorders characterized by ineffective ematopoiesis and dysplasia. In MDS, genomic abnormalities accumulate in a hematopoietic stem cell leading to peripheral cytopenias of varying degrees of severity, as a consequence of multilineage differentiation impairment, and in the early phases, bone marrow (BM) apoptosis. Morbidity and mortality in the disease results form cytopenias or transformation to acute myeloid leukemia, which may both lead to serious infectious diseaes, anemia or hemorrhage caused by dysfunciton and reduction of blood cells. Cytopenia (low blood cell count) resutls form a high rate of apoptosis within the bone marrow environment and consequent lack of release of cells into the periopheral blood circulation. (Albitar, US Patent No: 10,604,801).
Diagnosis of MDS:
Proepr abnd early diagnosis is very important for treating and managing progression of MDS becasue a chance for remission is much higher if MDS is detected prior to the stage where it has progressed to leukemia. Diagnosing MDS can be cahllening, especially during early stages when a patient’s symptoms include cytopenia without an increase in blasts. Tehre are numerous reactive processes that cause cytopenia including drug reaction, nutritional or hormonal deficiencies, and autoimmune diases or chronic infection. The majro criteria for diagnosing MDS are the presence of periopheral cytopenia and dysplasia. However, evaluating dysplasia is subjective and can be difficult without bone marrow biopsy. It was discovered that periopheral blood plasma is enriched with tumor specific DNA in patietns with MDS. DNA is beleived to be due to the relatively high apoptosis of neoplastic cells in MDS. These neoplastic cells die in bone marrow and rleease their DNA in circulation. Most likely this DNA is in the form of apoptotic bodeis, microvessels or protein-DNA complex. (Albitar, US 10,227,657)
–Next Generation Sequencing (NGS) on cell-free DNA:
Albitar, (US 10,227,657) disclsoses a method of treating a patient for myelody plastic syndrome (MDS) that includes a step of identifying the patient as an MDS patient by performing a mutation analysis comprising next geenration sequencing (NGS) on cell-free DNA from the patient’s periopheral blood plasma or serum. In some embodiments, the mutation analysis is performed on MDS assocaited genes such as ASXL1, ETV6, EZH2, IDH1, IDH2, NRAS, CBI, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF1 and ZRSR2. NGS analysis includes any DNA sequencing method which is performed by adhering a DNA sample to a solid substrate and without separating DNA molecules according to their lenght by electrophoretic gel. In some embodimetns, the NGS can be performed with ILLUMINA (SOLEXA) SEQUENCING kit, ROCHE 454 SEQUENCING, ION TORRENT: PROTON?PGM SEQUENCING (Thermofisher) and SOLID SEQUENCING (Thermofisher). (Albitar, US 10,227,657)
Treatment:
Known treatments that can be adminsitered to a patient diagnosed by the NGS mutation anlysis include transfusion therpay, erythropoiesis-stimulating agents, antibiotics, drug therapy, chemotherpay with or without stem cell therapy, entry into clinical trials or a combination thereof. (Albitar, US 10,227,657)
Myeloproliferative Neoplasms (MPNs):
MPNs are chronic myeloid cancers that are characterized by the overproduction of mature blood cells, and that may evolve into acute myeloid leukemia. In addition to chronic myeloid leukemia with the BCR-ABL fusion gene, the three most common myeloproliferative neoplasms are essential thrombocythemia, polycythemia vera, and myelofibrosis. (Albitar, US Patent No: 10,550,435)
Diagnosis of MPNs:
Chronic myeloproliferative neoplasms (MPNs) are diagnosed and confirmed by morphologic and characteristic molecular abnormalities. Almost all cases with polycythemia vera (P-Vera) are characterized by a mutation in MAK2. Primary myelofibrosis (PMF) and essential thrombocythemia (ET) show JAK2 mutation in 40% of cases and MPL gene mutation in 2% of cases. Tests for these JAK2 mutations have greatly simplified the diagnosis of MPNs and are part of the standard screenign mechanisms. However, distinguishing essential thrombocythemia with nonmutated JAK2 form teh more common reactive thrombocytosis remains a diagnostic challenge. Albitar, US Patent No: 10,550,435)
Somatic mutations in the calreticulin gene CALR are detected in periopheral blood in 65-85% of essentail thrombocytheia (EG) and primary myelofibrosis (PMF) thatients that are JAK2 and MPL mutation negative. Moelcular anlysis of these three genes now allows these markers to be identified in >90% of MPN patients, helping to classify the disease and differentiate it form a reactive process. CALR mutation testing also has prognostic value as CALR mutations are assocaited with longer survival and fewer thrombotic evens compared to JAK2 mutations. Calreticulum is a calcium-bhding protein invovled in signaling and protein expression taht is believed to be responsbile for clearing misfolded prtoeins and involved in expression regulation. CALR mutations reported in myeloproliferative neoplasms create translation frameshifts in exon 9 which truncate the C terminal calcium binding domain and create a novel C-terminal peptide. Albitar, US Patent No: 10,550,435)
–Fragment Lenght analysis (FLA) of circulating tumor DNA (ctDNA):
A non-invasive method for disease monitoring is through analyzing tumor derived circulating DNA found in blood plasma. Circulating DNA in blood palsma can be found either as cell free circualting tumor DNA (ctDNA) or in circulating tumor cells (CTCs). The current udnerstanding is that tumors udnergoing necrosis or apoptosis may depsit cell free fragmetns of DNA into the bloodstream, which may correlate with prognosis and tumor staging. Fragment lenght analysis (FLA) is a reliable technique for detecting mutations such as JAK2 V617F mutant allele and JAK2 V617F mutations. Albitar, US Patent No: 10,550,435)
Albitar, (US Patent No: 10,550,435) discloses a method for screening a patient for a myeloproliferative neoplasms which incldues extracting cell free DNA from periopheral blood plasma or serum, performing fragment lenght analysis of calreticulin human gene (CALR) in the cell free DNA and determining tumor laod and biallelic mutation in calreticulin human gene (CALR). At least in some embodimetns, the fragment lenght analysis includes a step of labeling CALR fragments with one or mroe fluorescent dyes, amplifying the labeled fragmetns using PCR, separating the labeled fragments by size using capillary electrophoresis and analyzing the data using software to determine the size of the amplified labeled fragments and genotype.
Non-Hodgkin’s and Hodgkin’s lymphoma (NHL): See B-cell lymphomas on right hand panel.
Neuroblastoma:
Treatment:
Anti-Ganglioside GD2:
Neuroblastoma is one of the most common solid tumors in children. Over 95% of the pateints present with non-resectable primary tumors and disseminated metastasis to distant organ sites at diagnosis. The overall survival rate of such patients has not been significanlty imporved during the last 20 year despite high dose chemotherapy follwed by allogeneic or autologous hematopoietic stem cell transplantation and differentiation therapy with 13-cis retinoic acid. One concept in the treatment is targeting of tumor cells with mAbs directed against the glycolipid antien ganglioside GD2, which is pexressed at high desnity in most neuroblastoma cases. In contrast, limited expression bhas been detected in normal tissues. A variety of murine and human mouse chimeric anti-GD2 antibodies have been generated. such as CH14.18. (Zeng, Molecular Immunology 42 (2005) 1311-1319).
Ganglioside GD2 is a glycolipid that is strongly expressed on the surface of nueroblastoma cells. There is little intra or intertumor heterogeneity of the GD2 expression. The ch14.18 antibody is a chimeric construct using murine variable region H and L chain genes and human constant region genes for H IgG and L chain kappa. This antibody binds GD2 and activates complement. It mediates ADCC jby neutorphiles and NKs and lymphokine activated killer (LAK) cells. (J Clin Oncol 27:85-91, 2008).
Mesothelioma is a rare and aggressive cancer.
Non Hodgkin’s Lymphoma (NHL):
NHL is a broad category encompassing 20 different malignancies of B-cell or T-cell origin, which vary considerably in proliferation rate, histology, immunophenotype, cytogenetics, and ultimately in response to therapy. Since the early 1980s, following the first report of Burkitt’s like lymphoma in homosexual men, there has been a steady increase in the reported incidence of NHL developing in patients with AIDS. Cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) has been the standard of therapy for aggressive NHLs, curidng greater than 30% of patients with diffuse large-cell NHL. A cHOP/rituximab comnbination has also become a popular regimen based on results from separate phase II/III trials evaluating the combination using different schedules in elderly patients with aggressive B-cell NHLs. Ritximab is a chimeric antibody that binds to the CD20 antigen, which is expressed on a majority of B-cell lymphomas.
Skin cancers See outline
Renal cell carcinoma (RCC) accounts for about 3% of all adult malignancies in the US and is a clinicopathologically heterogeneous disease that includes several histologically distinct cellular subtypes. Evidence suggests that proximal renal tubules are the sites from which malignant RCC cells originiate, although such cells may also originate from distal tubules. A number of genetic syndromes predispose to the development of RCC (US 2009/0258002).
Thyroid Cancer: is the fastest growing cancer in the US with an estimated 46k plus new cases expected in 2012 according to the American Cancer Society. Diagnosis is by thyroid nodule fine needle aspirations (FNAs), a minimally invasive procedure to extract suspicious cells for examination under a microscope. However, FNA produces ambiguous results in up to 30% of cases. Because thyroid cancer is highly treatable, current guidelines recommend that most of these patients undergo thyroid resection for a definitive diagnosis. Post-surgical results, however, show that only 20-30% of these patients have the cancer. A company called Veracyte is using expert cytopathology of thyroid nodule FNA samples together with the company’s Afirma Gene Expression Classifier to resolved indeterminate results and thus avoid unnecessary surgery. Genzyme is also developing and marketing thyrotropin alfa for infection for patients with well-differentiated thyroid cancer under the trademark Thyrogen®. Thyrogen® is approved in the US as an adjunctive treatment for radioiodine ablation of thyroid tissue remants in patients who have unergone a near total thyroidectomy for well differeniated thyroid cancer and who do not have evidence of metastic thyroid cancer.
Vaginal cancers are rare entitiels, which are frequently associated with cervical or vulvar cancers. The upper vagina seems to be involved in most instances. If the cervix is involved with an invasive cancer with concomitant vaginal involvement, it is diagnosed as a primary cervical caner with extension into the vagina. The incidence of the disease is between 35 and 90 years, with most seen in the 60-79 year age range. Depending upon where the carcinoma is located, extension with regard to lymph node metastasis mimics the adjacent organ. If disease is in the upper vagina, it follws a spead pattern of cervical cancer, with metastasis to the obturator, iliac, and hypogastric lymph nodes.
Treatment is tailored to the extent of the disease. Large cancers are treated initially with external irradiation, which hopefully will shrink the tumor so local therapy will be more effective. External irradiation in a dose of 4000-5000 cGy is given initially for bulky stage I and II cancers. Some type of local therapy is then used, which may consist of vaginal ovids or a similar applicaitonthat will cover the whole vagina, delivering a surface dose of 6000 cGy, or higher doses is two applicaitons are used. One study concluded that a tChimeric antigen receptor (CAR) T cell therapy:otal radiation dose over 75 Gy including brachytherapy does great than 30 Gy provide a significant increase in residual-free survival.
Depending upon the location of the primary tumor, the draining lymph nodes are also treated with external irradiation.
Pancreatic Cancer:
Pancreatic Ductal Adenocarcinoma: is resistant to current immuotherapies and remains one of the most letal cancer in humans. The resistance of pancreatic cancer to immunotherpay could be due in part to a paucity of neoantigen-reactive tumor-infltrating lymphocytes resulting form the low mutational buden of the diase; such lymphocytes may be critical mediators of immunotherpay responses in solid cancers. (Leidner, “Neoantigen T-cell Receptor gene therapy in pancreatic caner” NEJM, 382; 22, 2022.)
–-Cimeric antigen receptor (CAR) T cell therapy: targetting T-cell therapy targeting CD19 and B cell maturation antigen has revolutionized the treatment of hematologic cancers. However, the transfer of T cells that have been genetically enigneered to express CAR agaisnt overexpressed pancreatic-cancer antigens such as mesothelin, CD133 and epidermal growth factor receptor has been alrgely inefective in patients with pancreatic ancer. Leidner, “Neoantigen T-cell Receptor gene therapy in pancreatic caner” NEJM, 382; 22, 2022.
Leidner, “Neoantigen T-cell Receptor gene therapy in pancreatic caner” NEJM, 382; 22, 2022) disclsoes that a patient with progressive metasatic pancratic cancer was treated with a single infusion of 16.2×109 autologus T cells that had been genetically enigneered to clonally express two allogenic HLA-C*08.02 restricted T cell receptors (TCRs) tagetting mutation KRAS G12D expressed by the tumors. The pateint had regression of visceral metastases. The engineered T cells constituted more than 2% of all the cirulating periopheral blood T cells 6 months after the cell transfer. Note that HLA-C*08:02 is expressed by about 8% of white persons and 11% of black persons in teh US and by lower percetnages of persons in most other racial and ethnic groups, a situation that limits this therapy to a relatively low percetnage of potential patients. However, additional TCRs targeting KRAS G12D and other hot-spot KRAS mutants restricted by different HLA molecules that have been ienntified could extend TCR gene therapy agaisnt mutant KRAS to a larger number of patients.
Synovial Sarcoma:
Synovial sarcoma is a rare form of cancer in which malignant cells develop and form a tumor in soft tissues of the body. This type of cancer can occur in many parts of the body, most commonly developing in the extremities. The cancerous cells may also spread to other parts of the body. Each year, synovial sarcoma impacts about 1,000 people in the U.S. and most often occurs in adult males in their 30s or younger.
Treatments:
Treatment typically involves surgery to remove the tumor and may also include radiotherapy and/or chemotherapy if the tumor is larger, returns after being removed or has spread beyond its original location.
–TCR Targetting MAGE-A4:
TTecelra is also the first FDA-approved T cell receptor (TCR) gene therapy. The product is an autologous T cell immunotherapy composed of a patient’s own T cells. T cells in Tecelra are modified to express a TCR that targets MAGE-A4, an antigen (substance that normally triggers your immune system) expressed by cancer cells in synovial sarcoma. The product is administered as a single intravenous dose. Among the 44 patients in the trial who received Tecelra, the overall response rate was 43.2% and the median duration of response was six months.