Although there are more than 200 different types of cancer, four of them –breast, lung, colorectal and prostate — account 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).
Anal Cancer:
Introduction:
Compared with cervical cancer, anal cancer is rare among the general population. But in certain populations, its incidence was more than double that of cervical cancer prior to the initiatiamous intrapithelial neoplasia are also at increased risk to develop anal intrapithelial and invasive lesions. on of Pap screening and is increasing, while rates for cervical cancer continue to decrease. The populations at highest risk for teh development of anal cancer are mem who have sex with men (MSM), regardless of their HIV status. Other high risk groups include women and heterosexual men with HIV disease and those who are immunosuppresed for other reasons, such as organ transplantation. Prevention and ealry detection of cancer of the anal canal is important becasue of their impact on survival. Pateints with cancer localized to the anus have a 5 year survival rate of 80% whereas survival rates drop to 30% for those with metastatic dsiease. (Winkler “Anal cancer and cervical cancer screening: key differences” Cancer cytopathology, Feb 25, 2011).
Cause/Etiology:
As with cervical cancer, human papillomavirus (HP) is responsible for most cases of anal cancer. In fact, the NCI states that more than 90% of anal cancers are caused by HPV, which is also responsible for penile cancer as well as head and neck cancer.
Of the hundreds of strains of HPV, the two most often assocaited with anal cancer are HPV 16 and HPV 18. Both are targets of the HPV vaccine.
Transmission/Populations at risk:
No national oganizaiton has issued routine anal cancer screening guidelines for the general population. Howeve,r because people living with HIV are most at risk of HPV infection, the HIV Medicine Association of the Infectious Diseases Soceity of American (HIVMA) recommends that certain people such as men who have sex with men (MSM), women who have receptive anal sex or history of anormal cervical Pap results and people infected with HIV who have genital warts (condylomas) have anl Pap smears. The American Caner Society includes the following groups: (1) women who have had vaginal, vulvar or cervical caner (2) anyone who has ahd an organ transplant and (3) anyone with a history of genital warts.
Diagnosis:
Clinically, there are many similarities between anal and cervical HPV related squamous mucosal disease. The manifestations range from overt gross disease in the form of genital condyloma to more subtle, flat, intrapitheial lesions. Clinical approaches to the diagnosis of AIN also borrow from teh cervical cacner model and include the applicaiton of colposcopy to the evalutaion of the anal canal perianl region. (Winkler “Anal cancer and cervical cancer screening: key differences” Cancer cytopathology, Feb 25, 2011).
Digital anal-rectal exam (DARE): is an essential clinical tool in high risk individuals. This is because most early invasive and cancers are easily palpable by the examining finger, even in the absence of clinical symptoms, adn are marked by the presence of induration or thickening. Yet this low-cost, low-tech tool is woefully underused. (Winkler “Anal cancer and cervical cancer screening: key differences” Cancer cytopathology, Feb 25, 2011).
Cytology: The goal of anal cytology is to sample the entire anal canal thoroughly, including the transformation zone. The cell sample is collected by using a water moisened, synthetic fiber swab with a nonscored stick. The swab is inserted into the anal canal past the dentate line until it abuts the distal rectal wall. The cells are harvested by using a cirular motion as the swab is retracted while applying firm lateral pressure to sample the epithelium in the mucosal folds of the canal. Pateint collected sample have a slighly lower specimen adequency rate than provider collected samples but have a comparable sensitivity for detectin of AIN. Self collected anal samples have been used for the diagnosis of other STDs and may be more acceptable to some patients. (Winkler “Anal cancer and cervical cancer screening: key differences” Cancer cytopathology, Feb 25, 2011).
In a normal anal cytology sample, nucleated squamous cells of both superficial and intermediate type, anucleated squames, squamous metaplastic cells and recal colomnar cells are seen. Anucleate squamous cells are a normal componet and arise from sampling of the keratinized, distal portion of the anal canal. Anal cytology often udner represents the severity of lesions found on HRA guided biopsy. Even in experienced hands, the prospective diagnosis of ASCC is infrequent and challenging on cytology. (Winkler “Anal cancer and cervical cancer screening: key differences” Cancer cytopathology, Feb 25, 2011).
–Anal Pap Smear: screens for changes in squamous cells that linet he anus as well as the crvix. Changes in these cells may suggest that cancer is likely to develop or that cancer has already developed. The test is quick and simple. Using a moistened swab (similar to a cotton swab tu with a synthetic tip becasue cotton fibers can interfere with the sample) is used to collect cell samples from the anal canal by swabbing all surfaces of the anus and rectum. The swab is rotated 360 degrees, pressing it slighly against the skin and then withdrawn as it is cotinuing to rotate the swab. (see Cichocki, RN “What is an anal pap smear?” June 14, 2022).
Anal Pap smears do not test for HPV strains. Instead, they detect cell changes that may result from HPV invention. Currently, the only FDA approved HPV test is a cervical Pap smear.
The possible results are the following: (1) negative –all cells normal (2) unsatisfactor –test will need to be repeated, (3) ASCUS (Atypical Squamouse Cells of Undertermined Significance) –some atypical (or unusual cells are present. These may indicate infection or inflammation. (4) ASC-H (Atypical Squamous Cells, cannot exclude a High-Grade Anal Squamous Intraepithelial Lesion (HSIL). This could indicated mild abnormalities or something more severe. (5) LSIL (Low-Grade Anal Squamous Intraepithelial Lesion –some abnormal cells are present. (6) HSIL (High-Grade Anal Squamous Intraepithelial Lesion –severe abnormality of cells that could be precancerous. More testing will be needed. (7) Squamous Carcinoma: cells changes that may indicate cancer. A biopsy will be required. (see Cichocki, RN “What is an anal pap smear?” June 14, 2022).
If abnormal cells are found, depending o the grade one may need to be monitored or have further testing, which can include a digital anal exam (exam of he anus using gloved hands), a biopsy, or an anoscopy.
A Pap smear is jsut a screening tool, not a diagnostic test. Positive resutls does not mean one has or will develop cancer. Often, abnormal lesions resolve on their own and do not become cancerous.
–Anoscopy: is a test in which a small light instrument called an anoscope is inserted into the anus in order to illuminate the skin lining the anus and rectum. Often, a high-resolution anoscopy (HRA) will be recommended for a follow up to an abnormal anal Pap. This type of anoscopy is done with a high resolution instrument that can be more precise than a regular anoscopy.
HPV DNA testing: The use of HPV 16 type specific testing in HIV negative MSM may prove to be more useful becasue the presence of HPV 16 is so specific (92%) for high grade AIN, albeit at a lower sensitivity (35%). (Winkler “Anal cancer and cervical cancer screening: key differences” Cancer cytopathology, Feb 25, 2011).
High Resolution Anoscopy (HRA): is the equivalent of cervical colposcopy and uses the same basic principles and procedures. Dilute acetic acid, vinegar, is applied to the mucous membrane to highlight areas of abnormality, which turn white compared with the adjacent squamous epithelium. The colposcope provide magnification and a strong light source to facilitate identificaiton of potential lesions and to garget them for biopsy. Colposcopic feature sued to dientify abnormalities include acetowhitening, lesion margin and surface contoure, vascular changes of punctation and mosaicism, and Lugol iodine staining pattern. (Winkler “Anal cancer and cervical cancer screening: key differences” Cancer cytopathology, Feb 25, 2011).
Tissue biopsy: remains the gold standard for the diagnosis of AIN. However, jsut like cervical colposcopy, the perfromance of HRA as a diagnostic test depends on the ability of the colposcopist to adequately observe and correctly target lesions for biopsy. (On the basis of the expeirence of the group at UCSF, headed by Joel Palefsky, MD, there is a steep learning curve to come competetn in HRA. The Palefsky group at UCSF provdies an annual course in HRA (Winkler “Anal cancer and cervical cancer screening: key differences” Cancer cytopathology, Feb 25, 2011).
Prevention:
Studies of the efficacy of the quadirvalent HPV vaccine are underway.
Treatment:
Combined modality therapty (CMT) with radiation and chemotherapy is the godl standard for teh treamten tof localized anal cancer, although it can have significant side effects.
Badder Cancer:
Treatment:
On November 21, 2025, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex, Merck) with enfortumab vedotin-ejfv (Padcev, Astellas Pharma) as neoadjuvant treatment followed by adjuvant treatment after cystectomy for adults with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin.
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 most common clinical presentation.
Multiple myeloma is treated with chemo therapeutic agents that are often initially effective, only for the blood malignancy to return 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.
–Antibody-Drug Conjugates:
—-Blenrep (belantamab mafodotin -Glaxo Smith): is an antibody-drug conjugate treatment for relapsed/refractory multiple myeloma. It is a humanized IgG1K mAb against the B cell maturation antigen and a cytotoxic agent.
–Targeting E3 Ubiquitin Ligase:
—-Revlimid (lenalidomide -Bristol Myers): is an oral immunomodulatory drug that in combination with dexamethasone is indicated for the treatment of pateints with multiple myeloma. US revenues decreated 4% in 2024 primarily due to generic erosion. It changes the E3 ubiquitin ligase specificity to include new targets.
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)
Myelofibrosis is a rare blood cancer that affects about 1 in 500k people around the world. About 40% of MF patietns are anemic at diagnosis, and nearly all eventually develop anaemia and become dependent on regular blood transfusions.
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.
Treatment:
–Ojjaara/Omjjara (momelotinib -GlaxoSmith): is a JAK1, JAK2 and ACVR1 inhibitor for myelofibrosis with anaemia.
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 significantly improved during the last 20 year despite high dose chemotherapy followed 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 xpxressed at high density 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 (PDAC):
PDAC is the most common form of pancreatic cancer and it has a ismal 13% five year surfvival rate. PDAC is the third leading cause of cancer deaths. One major challenge to treatment is the fibrotic tumor microenviornment (TME) which is cahracterized by dense tissue that forms a barrier around the tumor, inhibiiting blood vessel formation and blocking immne infiltration. These effects contribute to chemo and immunotherapy failure.
PDAC has quickly risen to become the third leading cause of acner related death in the U.S. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. (Chibaya, “Nanopartcile delivery of innate immune agoists combined with senescence-inducing agents promotes T cell control of pancreatic cancer” Sci Trasl Med. 2024, 16(762))
PDAC is resistant to current immuotherapies and remains one of the most lethal cancer in humans. The resistance of pancreatic cancer to immunotherapy could be due in part to a paucity of neoantigen-reactive tumor-infltrating lymphocytes resulting form the low mutational burden of the disease; 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.)
Although immune checkpoint blockage (ICB) therapies targeting inhibitory checkpoints such as pgrammed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte assocaited prtoein 4 (CTLA-4) on T cells have demonstrated durable responses in some cancer types, they have not shown efficacy in PDAC. In addition pancreatic tumor cells themselves have poor immunogenicity and antigenicity, mediated in part by suppression of IFN signaling by ocogenic KRAS driver mutations. Chibaya, “Nanopartcile delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer” Sci Trasl Med. 2024, 16(762))
–-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) discloses that a patient with progressive metasatic pancreatic cancer was treated with a single infusion of 16.2×109 autologus T cells that had been genetically engineered 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.
–nanoparticle delivery of innate immune agonists combined with senescence inducing agents:
(Chibaya, “Nanopartcile delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer” Sci Trasl Med. 2024, 16(762)) discloses combing delivery of sitmulator of itnerferon genes (STING) and TLR4 innate immune agonists by lipid based nanoparticle co-encapsulation with senescence inducing RAS targeted therapies, which can remodel the immune suppressive PDAC TME through the senescence assocaited secretory phenotype. Treatment of transplanted and autochtonous PDAC nouse models with these regimens enahcned uptake of NPs by multiple cell types in the PDAC TME, induction of type I inteferon and other pro-inflammatory signaling pathways, increased antigen presentaiton by tumor cells and APC, and subsequent actiaiton of boht innate and adaptive immune responses.
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.
Uterine (Endometrial) Cancer:
Endometrial or uterine cancer is the most common gynaecologic cancer in developed countires. Globally about 1.6 million people live with active disease, and 417k new cases are reported each year. About 15-20% of patients have advanced disease when they are diagnosed.
Treatment:
–Anti-PD1 antibodies:
—-Jemperli (dostarlimab -Glaxo Smith): is an anti-PD1 mAb for endometrail, colorectal, ehad and neck and lung cancers. In combination with chemotherpay, Jemperli was approved for patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer. Phase III RUBY trail data showed that Jemperli and chemotherapty led to a 31% lower risk of death than those treated onoy with chemotherapy. In 2024, the FDA exapnded approval for Jemperli plus chemotherapy to include all pateints with primary advanced or recurrent endomethrial cancer.
Glaxo Smith’s targeted approach identified a specific biomarker, known as dMMR/MSI-H, that is present in some gynaecologic and other cancer tyeps, such as colorectal cancer.