Decipher Bladder by Veracyte which acquired Decipher early 2021 is genome analysis based diagnosis tool.
So far the usage for Decipher for bladder cancer is to predict if the patient's tumor will respond to platinum based (e.g. cisplatin) neoadjuvant chemotherapy before radical cystectomy. Decipher uses subtypes of the bladder cancer if it is luminal subtype or basal sub type by analyzing genome of the tumor. Urothelial carcinoma starts from the lining of the bladder. The lining of the bladder consists of a single layer of superficial cells, 5-7 layers of intermediate cells and a single layer of basal cells. Genome composition of normal superficial cells and normal intermediate cells are similar and classified as luminal subtype. Normal basal cells have different genome composition and classified basal subtype. There is a strong association that cancer cells with basal subtype respond well to platinum based chemotherapy. Decipher is an additional tool to help urologist/oncologist to determine if a patient should received neoadjuvant chemotherapy or perform radical cystectomy without neoadjuvant chemotherapy.
Immunotherapy drugs and Antibody Drug Conjugate (ADC) use antibody to deliver the drug to the cancer cells targeting specific protein which are highly expressed on the cell membrane of the cancer cell.
PADCEV delivers cytotoxin MMAE by first binding to NECTIC-4 proteins on bladder cancer cells. One draw back for ADC is that Antibody is a big molecule, which is has an approximate mass of 160–200 kDa. So, the development time is long. For example the chemical formula of pembrolizumab monoclonal antibody is C6534H10004N1716O2036S46. It consists of 6,534 carbon atoms, 10,004 hydrogen atoms, 1,716 nitrogen atoms, 2,036 oxygen atoms and 46 sulfur atoms.
Bicycle (R) by Bicycle Therapeutics in England has developed much smaller drug delivery platform compared to monoclonal antibody.
Bicycle is small, synthetic Bicycle Toxin Conjugate. The small size of Bicycles (1.5-3 kDa) which is 1/100 of monoclonal antibody allows rapid tissue penetration and extravasation. Bicycles are fully synthetic, allowing simple conjugation to form a Bicycle Toxin Conjugate, allowing targeted delivery of a cytotoxic payload. There is Phase 1 clinical trial for Bicycle Toxin Conjugate (BTC) with payload of cytotoxin MMAE, which is exactly the same toxin PADCEV used. So far, BTC with MMAE for bladder cancer has less side effects compared to PADCEV. Also Antibodies are broken up in liver but Bicycle is cleared by kidneys because of its small size.
For NMIBC continued
I have found another Phase 2 clinical trial of Pembrolizumab + CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF ( Granulocyte-macrophage colony-stimulating factor) which is a substance that helps make more white blood cells, especially granulocytes, macrophages, and cells that become platelets.
Oncolytic vaccine (adenovirus based) is common cold virus which had been attenuated engineeringly so patients will not get sick but retains virus features that once it gets into the cell it multiplies and burst the cell. Cancer cells often have impaired antiviral defenses that make them susceptible to infection to virus. So, Oncolytic vaccine is considered as cancer targeted treatment. Bladder cancer treatment wit oncolytic virus is not new.
instiladrin (rAd-IFNα/Syn3, nadofaragene firadenovec) by Vivienta Bio, which is a replication-deficient recombinant adenovirus vector encoding IFNα-2b with anti-tumor activity is already Phase 3 and the efficacy results demonstrated that 53.4% of patients with CIS demonstrated a CR at 3 months, and 24.3% of patients maintained disease-free at 12 months after intravesical instiladrin treatment. Even more favorable results were observed in patients with papillary-only disease (12-month CR rate of 43.8%). Instiladrin is give intravesically into bladder. clinicaltrials.gov/ct2/show/NCT00462488
For advanced and metastasized bladder cancers
Pembrolizumab (Keytruda) PD-1 immune check point inhibitor had been approved for advanced and metastasized urothelial carcinoma back in 2016 as the 2nd line treatment when the first line treatment by platinum based chemotherapy (eg. cisplatin) had failed. Since then, several pharmaceutical companies introduced their version of immune check point inhibitors (PD-1, PD-L1) for a specific application.
In recent years, Avelumab (BAVENCIO(R)) PD-L1 checkpoint inhibitor by Pfizer was approved as maintenance therapy in which Avelumab is administered every 2 weeks, now double dose every 2 weeks also, right after platinum based chemotherapy rather than waiting for the chemotherapy to stop working. Note that to qualify for Avelumab, the cancer must have improved or stayed the same during the chemotherapy.
In August 2021, FDA approved Nivolumab (OPDIVO) by Bristle Meyer Squibb (BMS) as adjuvant immunotherapy within 120 days after radical chemotherapy. Nivolumab had been approved in the same year Pembrolizumab in 2016. Nivolumab and Pembrolizumab are PD-1 immune check point inhibitors. Note that MERCK infringed the patent owned by BMS and paid $625M and still paying 6% royalty to BMS.
There are two ADCs have been approved in the US. One is PADCEV and the other is Trodelvy.
enfortumab vedotin (PADCEV (R)) by Seagen Inc and Astellas is monoclonal antibody drug conjugate which utilize human based antibody which targets NECTIN-4 proteins which are expressed high on the cell membrane of bladder cancers. Once PADCEV reaches the cancer cell, it infuses payload of cytotoxin chemo agent MMAE (monomethyl auristatin E), which is synthetic form of toxin extracted from the sea hare. MMAE prevents mitosis in the cell cycle by disrupting the formation of microtubules, which leads to the cell death.
sacituzumab govitecan (Trodelvy(R)) by Gilead Science was approved in September, 2021. Trodelvy binds to Trop-2, a protein located on the surface of cells, is overexpressed in urothelial carcinoma as well as other solid tumors. Once Trodelvy binds to Trop-2 of cancer cell, it infuses cytotoxin govitecan, which is a synthetic form toxin extracted some plant which is found only in Asia, especially in China. Govitecan will prevents unwinding of DNA in S phase in the cell cycle during the cell division, which leads the cancer cell to death.
Erdafitinib (Balversa) of Johnson & Johnson is a targeted kinase inhibitor that exerts its action by binding to and blocking the enzymatic activity of several cell proteins, including fibroblast growth factor receptors FGFR1, FGFR2, FGFR3, and FGFR4. One study says in urothelial carcinoma, they found FGFR3 fusions 6%, FGFR3 mutations 10-60%, FGFR1 amplifications, which increase proliferations of cancer cells.
I have not checked if there are clinical trials for ADC with different cytotoxin payload or other Kinase inhibitors.