Tror de brukte ulike protokoller for evaluering av tumorrespons i den originale studien fra 2015 og 5-års oppdateringen. Virker som de brukte RECIST 1.1 i den første publikasjonen og irRC i 5-års oppdateringen. UV-103 bruker irRC såvidt jeg vet. Så det er mulig at dette også driver noe av forskjellen i respons mellom de to publikasjonene. Har ikke klart å finne ORR basert på irRC i den originale publikasjonen på keynote-006.
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Men påvirker det egentlig antallet CR? Er ikke hovedpoenget med irRC at det tillater “pseudoprogresjon” uten at det teller som en PFS-event? Fordi det tar tid for immunterapi å virke? At det altså påvirker PR, PD, SD og ORR. Men en CR er vel en CR?
Jeg vet ikke, kjenner ikke litteraturen godt nok rundt dette. Kan hende det finnes studier der man sammenligner recist 1.1 or irRC. Men det virker jo plausibelt at man kan få lavere andel av spesielt PR, men også CR hvis man mister pasienter til PD som egentlig var pseudoprogresjon eller at baseline blir endret. Men det er veldig vanskelig å vite sikkert. I Keynote-006 virker det som de hadde en hybridløsning der de både brukte irRC og recist 1.1, som kanskje igjen gir mindre forskjell? Derfor jeg håpet at de skulle oppgi ORR basert på irRC i den originale publikasjonen.
Det blir jo ikke fair å sammenligne ORR basert på to ulike målemetoder. Tror også kun ORR basert på recist 1.1 var basert på sentral review, men det er jeg ikke 100% sikker på. Samtidig er det heller ikke fair å sammenligne to studier på ulike tidspunkt hvis det kommer responser lang tid etter oppstart med keytruda.
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CR etter irRC er “Complete resolution of lesions (confirmed at 4 weeks) from first irCR scan”
CR etter RECIST 1.1 er “Complete resolution of non-nodal lesions and < 10 mm short-axis for lymph nodes”
Blir jo ikke noe annerledes det? Om noe, så er jo kravet til CR med irRC strengere.
Enig i at noen CR kan ha blitt klassifisert som PD etter RECIST 1.1 i den første rapporteringen. Men en PR som senere blir en CR vil jo ikke bli borte i RECIST 1.1 heller, fordi det er “best overall response” man rapporterer.
Man kan selvsagt gå fra PR til CR det sier jeg ingenting på. Jeg tenker på de som får PD med recist 1.1 og at terskelen for å få PD er høyere med irRC. Men de har som sagt brukt en hybridløsning så det er vanskelig å spå hvordan dette ville slå ut.
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Vi kan nå gravlegge nok en potensiell konkurrent til UV1. Det franske selskapet Invectys utviklet i likhet med Ultimovacs en peptidebasert universell kreftvaksine med hTERT som mål, kalt UCPVax. Denne er nå fjernet fra deres pipeline. De tre pågående studiene med UCPVax som drives av et akademisk miljø på universitetssykehuset i Besancon under ledelse av Olivier Adotevi ser på clinicaltrials ut til å fortsette, men Olivier Adotevi har gått ut av Scientific Advisory Board i Invectys. UCPVax virker dermed nå som 100% et akademisk prosjekt uten plan for kommersialisering.
Invectys hadde også en DNA-basert vaksine under utvikling. Den har de nå omdøpt fra INVAC-01 til IVS-2001 på websiden deres. Men det er også det eneste som har skjedd siden MD Anderson terminerte en studie med den i 2020. Så det virker rett og slett som denne ballen også er lagt død.
Vi står da igjen med en eneste reell konkurrent, og det er Inovio og INO-5401. På clinicaltrials står studien i blærekreft som fortsatt aktiv, men den er i realiteten terminert. Det eneste man har av data, er fra en fase II i glioblastoma med 54 pasienter, som hadde første interim for to år siden. Det ble presentert ytterligere data fra denne nå i sommer, som vel heller ikke var fantastisk lovende: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.2004
Uten å ha noen videre konkrete planer for å vise terapeutisk effekt av denne vaksinen, så har de (som jeg også skrev for lenge siden) satt i gang en liten fase I med 44 pasienter som inkluderer friske pasienter for å undersøke INO-5401 i en profylaktisk setting. INO 5401 Vaccination in BRCA1/2 Mutation Carriers - Full Text View - ClinicalTrials.gov Det er derfor vi er så utålmodige på UV2, de Sousa! 
En litt mer tilgjengelig versjon av siste data fra INO-5401:
Det er også verdt å merke seg at INO-5401 er en videreutvikling av den nå skrinlagte INO-1400. INO-1400 var helt universell, mens INO-5401 ikke er det.
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Hørte Sousa (eller Bjørheim) forklare i grove trekk forskjellene mellom UV1 og andre konkurenter en gang, men hva er forskjellen på UV1 og disse konkurentene? Hva er det som gjør at vi mener UV1 fønker, når de andre legges døde?
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En slide fra rundt IPO sier en del om det:
Og samtlige av disse er altså nå lagt døde! UV1 er det eneste treet som er igjen i dette landskapet:
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Edison har en veldig god introduksjon til hva som er unikt med UV1:
hTERT vaccines and how UV1 is different: Cancer immunotherapy and rationale for cancer vaccines
During a malignant process, as cancer cells die the composite proteins/antigens are taken up by a patient’s own antigen-presenting cells, such as dendritic cells or macrophages, and presented to T-cells. This can lead to the activation and production of populations of T-cells capable of recognising and attacking cancerous cells that display the antigens. However, this process is not perfect, which is why not every malignant process is stopped. Once a tumour develops, it often also has multiple ways to suppress an immune response and enable the tumour to evade immune cells. The goal of cancer immunotherapies is to expose the tumour microenvironment (TME) as foreign to the patient’s immune system, so the tumour is recognised, immunologically attacked and turned from ‘cold’ to ‘hot’.
CPIs were the first successful approved cancer immunotherapies that changed treatment paradigms in many solid cancers. Although very effective in certain subsets, many patients do not respond to this treatment, as CPIs rely on existing cancer-specific T-cells. In cases where the T-cells are not primed, the consensus in the immunoncology community is that there is a need to find ways to increase the supply of such primed, cancer-specific T-cells. One approved and successful approach is CAR T-cells, where the T-cells are taken from the patient via apheresis, genetically modified to recognise the cancer, then administered back to the patient. Although very effective in certain leukaemias, this process is complicated, long and costly.
The search for effective immunotherapies led to the exploration of different approaches, one of which is cancer vaccines. Various options explored so far include peptide-based, oncolytic viruses and allogeneic or autologous dendritic cell vaccines, but Dendreon’s Provenge (dendritic cell vaccine, approved in 2010) and Amgen’s Imlygic (oncolytic virus, approved in 2015) are the only approved cancer vaccines. The relative lack of more successful examples, however, could be explained by the variability in vaccine design, antigen selection and understanding of the inhibitory barriers presenting by immunosuppressive TMEs. In addition, more and more preclinical studies support the idea that the backbone strategy in immunoncology should be combination treatments exploiting different steps in the immunity cycle (Schlom and Gulley, 2018).
Peptide-based cancer vaccines, such as UV1, work by presenting antigenic material expressed by the cancer and aim to strengthen the ability of the immune system to recognise and eliminate the malignant cells. Because peptide vaccines act as immune primers, it is rational to combine them with therapies that act late in the cancer immunity cycle, such as CPIs. Various peptide vaccines have also been shown to be well tolerated in early trials. This characteristic will be crucial in combining them with CPIs with known side effects that have presented hurdles to developing double or triple CPI combinations.
Cancer antigens can be divided into two broad categories. Tumour-specific antigens (TSAs) are only found in cancer cells, not healthy cells. Tumour-associated antigens (TAAs) are peptides from normal proteins, which are overexpressed when cancer develops. So, peptide vaccines that are developed using TSAs are patient specific, which means this type of therapy is highly personalised and involves very complicated logistics. Because of this complexity, few attempts have been made to progress them into the clinic. Peptide vaccines that use TAAs can be used in all patients who have cancers with known overexpressed TAAs. These types of vaccines have the advantages of being convenient, off-the-shelf, manufacturing costs are low, and logistics and administration (subcutaneous) are straightforward.
hTERT: A hallmark of cancer
Telomeres provide cells with a mechanism that prevents the abnormal proliferative capacity that can lead to the development of cancer. During normal cell division, chromosomes are capped with sections of so-called telomeres that are not fully replicated and gradually shorten after each cycle, causing a finite replicative capacity. TERT is one of two major components of the enzyme telomerase, which maintains telomere length in the dividing cells. One of the hallmarks of cancer is the ability to maintain telomeres in this process through the overexpression of hTERT, which enables cancer cells to replicate infinitely.
hTERT is expressed in up to 85% of all cancers (haematopoietic and solid) while being absent in most normal tissue and has been an attractive prospect for cancer immunotherapies with scope to treat a broad range of cancers. hTERT is immunogenic and considered a universal TAA and has been focus of several vaccines that have reached clinical development across various solid tumours (Exhibit 2).
GV1001 is a peptide-based hTERT vaccine being developed by KAEL-GemVax and has been the most extensively investigated vaccine of this type. Collectively, trial data suggest hTERT vaccines are capable of inducing a T-cell response in patients, but broadly speaking, when used in mono therapy, this has been insufficient to effectively control cancer progression. Importantly, data so far highlight the minimal risk of adverse events with the strategy, potentially lending hTERT vaccines to combination regimens with other cancer immunotherapies, such as CPIs, where historically the potential for additive efficacy has had to be carefully balanced with additive toxicity.
We highlight data from the Phase III TeloVac trial,which investigated GV1001 with concurrent chemotherapy (gemcitabine plus capecitabine) as a first-line intervention for pancreatic cancer patients. Despite eliciting immune responses, the concurrent combination showed no improvement overall survival or progression-free survival/time to progression. Investigators speculated that for a cancer vaccine to be effective, sufficient time is required for an immune response to develop and the early metastasising and rapidly progressive nature of pancreatic cancer might partly explain the absence of efficacy for GV1001 in the TeloVac trial.
Finding the right epitopes is key: Learning from GV1001
Given hTERT is an intracellular protein and is not expressed on the surface of cells, it can only be recognised by T-cells through shorter peptide sequences (epitopes), which are antigenic determinant sections of antigens. These are processed inside cells and presented as part of the major histocompatibility complex (MHC), also called human leukocyte antigen (HLA). MHC class I molecules are recognised by CD8+ cytotoxic T lymphocytes (CTLs) expressing a complementary T-cell receptor and MHC class II molecules are recognised by CD4+ ‘helper’ T-cells. Cancer cells can present hTERT peptides recognised by either MHC I or II and peptide-based vaccines developed to date have been designed for both epitope classes.
Although inducing an MHC class I response and activation of CD8+ CTLs through immunisation is considered the major mechanism for inducing an antitumor immune response, insufficient CD4+ T activation can lead to dampening of this. Hence, induction of an MHC class II immune response and CD4+ T activation can enhance the ability for CD8+ CTLs to attack tumours, but also promote immunological memory that translates to long-term cancer immunity.
So far, many peptide cancer vaccines have been aimed at activating CD8+ T-cells via MHC I. Given the lack of encouraging clinical data with this approach, as described above, CD4+ T-cell influence in anticancer immune response is receiving renewed interest in the scientific community. UV1 contains three long peptides, so it induces hTERT specific CD4+ T-cells (via MHC II) producing cytokines associated with T helper cell type 1 (Th1) immune responses, which triggers a strong anti-tumour immune response and expansion of secondary effector cells, including induction of CD8+ anti-tumour T-cell response.
Findings from a long-term follow-up of a Phase I/II trial of GV1001 in NSCLC patients guided the design and composition of UV1, which can be considered a second-generation hTERT vaccine that is distinct and unrelated to GV1001. Blood samples from these long-term survivors in the trial showed expression not only of GV1001-specific T-cells, but also T-cells primed to distinctly different hTERT-derived peptides, which were not part of the GV1001 vaccine. Crucially, the patients, who had these T-cells primed for non-GV1001 hTERT-derived peptides also demonstrated improved survival. The patients, who did not have these T-cells, did not show the clinical benefit from the vaccination, although they did demonstrate T-cell response against GV1001 peptide. UV1 consists of these peptides (hTERT691-705, hTERT660-689 and hTERT652-665). Ultimovacs’ hypothesis is that because T-cell responses against these peptides were only observed in patients with a favourable clinical course, it indicates these specific peptides could be responsible for the tumour eradication in patients.
The three long peptides that UV1 consists of have been shown to contain multiple T-cell epitopes that can fit with the HLA type of the vaccinated patient. Data from numerous patients’ samples indicated there is no HLA bias and immune responses against the vaccine peptides occur across multiple HLA allele types (the peptides are promiscuous with respect to HLA). Therefore, the UV1 vaccine peptides ensure broad population coverage, circumventing the need for HLA screening.
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Ah. Hadde helt glemt den. Den der er strålende. Takker for påminnelse.
Så dumt at du slettet innlegget akkurat når jeg skulle lese histogrammene 
Jeg ble gjort oppmerksom på at KM plottet jeg brukte ikke nødvendigvis er 100% representativ . Poster den igjen på småprat straks med presisering rundt det.
Oppdatering : Her er lenken:
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For ordens skyld
Ultimovacs Announces Completed Patient Recruitment in TENDU Phase I Clinical Trial in Prostate Cancer
- First clinical trial based on Ultimovacs’ proprietary TET adjuvant platform
technologyFirst clinical trial based on Ultimovacs’ proprietary TET adjuvant
platform technology- 12 patients with prostate cancer treated in TENDU study
- Study provides immune activation and safety data important for future
clinical development within the TET technology
Oslo, 14 December 2022: Ultimovacs ASA (“Ultimovacs”) (OSE ULTI), a clinical-
stage biotechnology leader in novel immunotherapeutic cancer vaccines, announced
that last patient enrollment has been completed in the Phase I TENDU trial in
prostate cancer. Patients with relapse after primary radical prostatectomy
received four doses of the TENDU vaccine during a 6-week treatment period. Three
different dose levels have been explored (40, 400, 960 mcg) and half of the
patients were treated at the highest dose level.
“We are pleased to have completed the enrollment of patients in the first
clinical trial based on the TET platform technology”, said Carlos de Sousa,
Chief Executive Officer at Ultimovacs. “The TET platform represents an
innovative approach that can provide the flexibility to incorporate different
antigens in vaccines relevant in different tumor types and stages.”
The TENDU clinical trial is the first trial based on the Ultimovacs’ novel
vaccine-adjuvant platform, TET (Tetanus-Epitope Targeting). The technology
combines the two key components of a vaccine in a single molecule, the cancer-
specific antigens and the immune response strengthening adjuvant. The primary
objective of TENDU is to evaluate safety and tolerability of different doses of
the vaccine in patients with progressive disease after prostatectomy. No safety
concerns have emerged in the on-going study. All patients are followed up for 6
months after the last treatment.
“The evidence to date indicates that the TET vaccine-adjuvant platform has the
potential to be a highly flexible platform, which can be effectively combined
with many therapeutic approaches in oncology,” said Jens Bjørheim, Chief Medical
Officer at Ultimovacs. “The data from the TENDU trial will be valuable in
exploring the opportunities for future development of a clinical program based
on the TET platform technology.”
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Fikset 
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På hugget for tiden 
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Da er UV2-patentet publisert folkens!
WO2022258794 - A CONJUGATE
“the polypeptide or the combination is for use in the treatment or prophylaxis of cancer”
Det som er ekstra interessant er at det beskrives flere alternative polypeptider basert på hTERT. Om det er for å lage patentet så bredt som mulig for beskyttelsen sin del, eller om det er for at man faktisk kommer til å gjøre endringer fra peptidene fra de som brukes i UV1 er uklart.
WO2022258794-APBDY-20221215-1214.pdf (13,0 MB)
Dette patentet har prioritetsdato 09.06.2021, som betyr at man har beskyttelse helt til 08.06.2042 - og DET er lenge det!
Edit: For de som ikke har det helt klart for seg, så er altså TET+UV1=UV2
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Flott Sånt må jo aksjen bare straffes for 
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Dette innlegget ble rapportert og er midlertidig skjult.
Takk for info. Strålande