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Personalized tumor vaccine shows promise in pilot trial
Vaccine against patients' own tumors triggers a broad response, and induced five-year remission in one patient with advanced ovarian cancer
https://eurekalert.org/pub_releases/2018-04/uops-ptv041118.php?utm_content=70057331&utm_medium=social&utm_source=twitter
Nivo acts like a vaccine in Neoadjuvant PD-1 Blockade in Resectable Lung Cancer study
In pretreatment blood samples, specific T-cell responses were detected against 19 of the 47 candidate mutation-associated neoantigens,
7 of which were still detectable at day 44. In addition, 7 new mutation-associated, neoantigen specific T-cell responses had developed by day 44
http://www.nejm.org/doi/full/10.1056/NEJMoa1716078?query=featured_home&
I was hoping for a second opinion.
Neon needs albumin-Binding, Lymph Node Targeting Amphiphile Technology from Vedantra to complete their PCV vaccine. Sellas must have reviewed head to head comparison before picking the Lm platform.
CCP just shut down an Android app downloaded 200 million times. The developer had to apologize for being too good. I don't know how Americans can invest in a country where common laws don't work.
You can add Neon to that list. Which one of these will have IND in 2018? Do you know why Sellas didn't use poly-ICLC as adjuvant? Why bother waiting 2 years for ADXS to come up with a WT plasmid?
HOT can be administered after KRAS screening. No waiting 8 weeks, good for pancreatic, colon..., ADXS HOT is likely ahead of Neon select. What other outfits are targeting hotspots?
I think ADXS31-142 + PD1 combo will mirror cabo on prostate cancer. Patients with higher PSA get better results, resolution of bone met etc.
I expect ADXS-503 (a clinical ADXS-HOT construct) to cover all seven mutations in the KRAS gene.
KRAS mutations are particularly common in colon cancer, lung cancer, and pancreatic cancer.
https://www.mycancergenome.org/content/disease/lung-cancer/kras/
It is all about front running. If you knew Fidelity was putting it's chips on Neon instead of ADXS, what would you do?
HOT will be in NSCLC soon. KRAS is mutated in almost 25% of adenocarcinoma patients. Around 50% of KRAS-positive lung cancers contain the G12C mutation.
https://lungevity.org/for-patients-caregivers/blogs/experts-blog/kras-mutations-in-lung-cancer-are-we-close-to-targeting
AACR:
our proprietary ADXS-503 (a clinical ADXS-HOT construct) which includes KRAS G12D as one of its multiple targets, was also capable of significantly suppressing tumor growth in the CT26 tumor model.
Neon NEO-PV-01 + Nivo combo 2 metastatic melanoma patients findings:
neoantigen-specific CD4 and CD8 T cell responses that were predominantly observed following vaccination. Vaccine-induced, neoantigen-specific CD8 T cells had an effector memory and central memory phenotype, secreted IFN?, TNFa and IL2, and were cytolytic. Finally, induction of neoantigen-specific immunity by NEO-PV-01 led to epitope spreading of the immune response to neoantigens not included in the vaccine.
Presenter matters when APC is targeted. One can block all CD47 on tumors resulting in little response. I think Lm is the best presenter, Neon knows it and is working on delivery.
Lm-19 & Lm-20, targeting 19 non-immunogenic and 20 immunogenic NSMs respectively. The ability of Lm-19 and Lm-20 to control MC38 tumor growth was evaluated in C57BL/6J mice. We found that both Lm-19 & Lm-20 led to an accumulation of neoantigen-specific CD8+ TILs and significantly slowed tumor growth.
Neoantigen load also associated with higher content of CD8 T cells, M1 macrophages, and CD4 memory T cells, and lower Treg, mast, dendritic, and memory B cells in multiple tumor types
http://www.cell.com/immunity/fulltext/S1074-7613(18)30121-3
Personalized Cancer Vaccines to Conquer Cancer
In the future, a person might be able to walk up to a clinic, get sequenced and then in a relatively short amount of time have a vaccine made for them.
https://www.parkerici.org/2018/04/11/personalized-cancer-vaccines-to-conquer-cancer/
$ADXS HOT + aCCR8 combo appetizer, NEO main course?
Lm-AH1 and aCCR8 combination therapy enhanced antitumor efficacy and prolonged survival
https://www.advaxis.com/wp-content/uploads/2018/04/KeystonePosterCCR8-combo-posterFINAL.pdf
What is nonrandom cluster of mutations?
the higher frequency of histone mutations than previously reported, significant co-occurrence within patients, identification of hotspots across histone gene families, recurrent mutations in conserved H2B phosphorylation sites, and identification of nonrandom clusters of mutations within 3D space support the growing body of data that suggests histone gene mutations play an important role in FL.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270390/
If some hotspot cancer mutations turn out to be frameshift mutations, ADSX can figure out many of the combinations and put the corresponding antigens into a plasmid. The large number of antigens Lm plasmids can carry may turn into a competitive advantage.
I don't know much about conspiracy, neoantigen prediction etc. CSO and CFO have more shares than most here, so their retention bonus would be peanuts if NEO pans out. If HOT is really waste of time, than Neon must also be a bunch of fools working on their Neon/select. Even if HOT is good for 10% tumor types, it still has significant value. Personally, I prefer ADSX to work on NEO/HOT POC with their cash, nothing else unless sponsor is found.
Moderna / Merck mRNA. Up to 15 predicted neoantigens will be selected , mRNA vaccine will be administered intramuscularly (IM) for four cycles every two weeks. A patient may receive a second course for a total of eight cycles given
https://clinicaltrials.gov/ct2/show/NCT03480152?term=cancer&lupd_s=03%2F15%2F2018&lupd_d=14
the real future for AMGN!! That is bullish. Any discussion on competitions? Roche is doing a 570 patients P1 study with their personalized vaccine.
Roche is injecting the adjuvant + mRNA into the lymph nodes. Couldn't SLS do the same with Poly-ICLC (Hiltonol) + GPS instead of waiting 2 years for a whole new vaccine. SLS should be adding adjuvant to current trials if they feel a booster is req'd.
Do you know why SLS wants ADXS to develope a WT1 vaccine? SLS can add Poly-ICLC (Hiltonol) to GPS just like what Neon and Roche are doing.
May be NEO can join this combo with another MOA.
GEM, Nab-P, D + T:
8/11 pts (73%) had a partial response, with the med duration of 7.4 months. Disease control rate was 100%. Med PFS was 7.9 months (95% C.I. 3.5-9.2 months). 6-month survival rate was 80% (95% C.I 40.9%-94.6%). Med OS has not been reached
http://abstracts.asco.org/210/AbstView_210_203275.html …
That is all part of the neoantigen prediction algo, supposedly upgraded and caused the 1 year delay. The key there is finding a highly immunogenic neoantigen. Neon may have an upper hand thru Catherine Wu/Dana-Farber conncection. I think ADXS NEO has better delivery and adjuvant.
Blueyecatch,
share price reflecting fear of dilution, uncertainty, chart painting!! AMGN had options and they picked ADXS so there is value in the Lm platform. Shorts will be naked after warrants expire, just in time to face some NEO data.
Thanks for the concise clarification.
If it has been 6 weeks from get-go, why would ADXS give a 16 week window from biopsy to patients? That is 10 more weeks for the mutating lesions.
Exclusion Criteria:
Is not expected to be available to receive study drug within 16 weeks from the time of baseline biopsy for any reason
12 weeks, not 18
Nivolumab at a dose of 240 mg administered by intravenous (IV) infusion over 30 minutes every two weeks. At Week 12, all patients, regardless of their disease status, will receive NEO-PV-01 + adjuvant administered subcutaneously (one vial of pooled peptides per injection site) in up to four distinct sites (each extremity or flanks) while continuing therapy with nivolumab.
That 1 year delay allowed ADSX to fine tune their process, lowering the Needle to needle time to 8 weeks, compared to 18 weeks for Neon.
PDAC will be a tough nut to crack
Following confirmation of mutation expression, a mean of 5 mutations (range: 4-6) were predicted to bind to MHC class I using multiple prediction algorithms (binding affinity <500nM). IFN? immunospot assay revealed a baseline immune response to one neoantigen in each patient
http://www.abstractsonline.com/pp8/#!/4562/presentation/8628
Will adjuvant be the deciding factor in the vaccine race?
Seven patients (88%) received a vaccine with ≥10 neoepitope peptides (median 12, range, 7-20), with median time to vaccine initiation of 18.6 weeks from surgery.
2 patients who did not receive dexamethasone during vaccine priming, generated robust de novo immune responses against multiple personal neoantigens. Circulating vaccine-induced polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses were enriched for memory and activated phenotypes, and increased numbers of tumor-infiltrating CD4+ and CD8+ T cells were detected in these 2 patients.
http://www.abstractsonline.com/pp8/#!/4562/presentation/8618
ADXS-NEO may obviate the need for a selection algorithm by using a brute-force approach. If "superfluous neoantigens—i.e. those not driving tumor growth—would act as decoys and make it harder for the immune system to locate the driver antigens." is true, high neoantigen burden should have resulted in lots of decoys and shown lowered anti-PD1 efficacy. Seems the authors of AACR abstract found no evidence of decoys.
"while having very high neoantigen burden, did not achieve complete response (2 PR & 1 PD). One of these patients had extremely high expression of IDO1, which may facilitate immune escape in a PD-1 independent manner. Two independent HLA mutations in HLA-A and HLA-B (stop-gain mutation and splice site mutation, respectively) were found in the second patient.."
There are different mutations such as germ cell mutation. Not everyone one of them results in neoantigen expressed on tumor cell surface.
Not a great day, a big pay day.
If NEO POC works out, AMGN will have to buy ADXS to take over HOT as well. In Neon's study, 20 peptides out of dozens neoantigens ID + PD1 yielded 100% remission in 6 melanoma patients. ADXS can put 2,3X peptides into HOT
If you kept on reading .... Applying this tool to the six patients’ tumor samples yielded dozens of unique neoantigens for each patient’s personal vaccine
Neon has to pick 20 out of dozen neoantigens and using novel adjuvant. ADXS NEO has no such limitation, proven adjuvant and tLLO to counter Treg. It seems to be a complete package.
From Dana-Farber:
"Since T cells can only recognize neoantigens that are “presented” to them by HLA molecules of the immune system, a key step in making the vaccine is using computer algorithms to predict which neoantigen peptides will bind strongly to the HLA molecules for recognition by T cells. Algorithms, such as NetMHC, have been developed in recent years, making it feasible to select HLA-binding neoantigen peptides for the vaccine. Applying this tool to the six patients’ tumor samples yielded dozens of unique neoantigens for each patient’s personal vaccine."
Is it because of antigen sink? T cell clones that target neoantigens don't have that issue and more of these the better outcome.
Highly significant association between neoantigen burden and response to anti-PD-1 therapy (PD + PR vs CR, P = 0.00046). We also observed that, in our cohort, response to anti-PD-1 therapy was more accurately predicted by neoantigen burden than mutational burden.
http://www.abstractsonline.com/pp8/#!/4562/presentation/7990
NEO related
Personalized neoantigen vaccine strategies in hematologic malignancies
http://www.abstractsonline.com/pp8/#!/4562/presentation/3673 …
I prefer ADXS to concentrate all the resources on NEO and HOT anyway. That seems to me where the real potential lies.