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Buying GNCA is not conventional wisdom
Refinitiv/Verus downgraded to sell. Wall St. analysts know CD not ACT
Lymphodepletion will remove the inhibitory T cells so high dose IL2 cohort should have a higher ORR. GEN-011 + lympho is the closest thing to T cell compartment restoration.
Buying GNCA is not conventional wisdom, none expects Gen-11 to work without anti PD1 except me
Schematic illustrating how functional antitumour responses are reliant on immune dynamics outside the tumour microenvironment (TME)
https://www.nature.com/articles/s41568-021-00347-z?utm_source=hybris&utm_medium=email&utm_content=e_alerts&utm_campaign=NRRJ_2_SJB_cancer_nr_newsletter&sap-outbound-id=DFC426FB709E09E4E53D298672A0CF83DB6F2838
Must read for longs.
SHC: It was definitely the moment when I learned that the weakest agonist peptide from the tumor, antigen TMEM161A, actually bound TCR2 with the highest affinity. Before this, I was leaning towards the general consensus that strong agonist peptides usually have strong binding affinities to the cognate TCRs, and obviously there are exceptions.
DT: It was the finding that some T cells in tumors cross-react to recognize pathogen-derived antigens and tumor antigens. This helped me better understand at a mechanistic level how immune recognition of pathogens may shape antitumor immunity.
https://acir.org/weekly-digests/2021/march/til-going-viral-detection-of-tcr-cross-specificity-for-viral-and-tumor-antigens
Looking at recruiting sites, we will get ORR on head and neck squamous cell carcinoma (HNSCC) and NSCLC this year. Few investors think GEN11 will work without anti PD1. A high ORR will debunk the conventional wisdom. The real workhorse is cytotoxic CD4+, not ICB.
Th-CTX were found in scRNA-seq datasets from breast, head and neck, and hepatocellular cancers. However, SLAMF7 was only upregulated in melanoma, breast cancer, and hepatocellular carcinoma – not in head and neck cancer.
https://acir.org/weekly-digests/2021/march/defining-cd4-t-cells-with-a-license-to-kill
Two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A+ tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient.
Another blow to conventional wisdom.
Among the study’s other findings was that patients least likely to respond to immunotherapy alone were those who responded best to the combined treatment. Patients, for example, who responded best had less of the chemical receptors (PDL1) on the surfaces of cancer cells that are blocked by pembrolizumab than patients who did not respond as well.
Researchers say further experiments are needed to determine how V937 changes the molecular makeup of the tissues immediately surrounding tumors.
https://nyulangone.org/news/perlmutter-cancer-center-study-shows-virus-therapy-holds-promise-against-inoperable-skin-cancers
Based on Penn CART T Cells and NCI melanoma T cells studies. I expect GEN -11 to beat that 33% by a mile. 3 simple reasons:
1. No bystanders in DP
2. T cells in DP are naive and more durable
3. Targets matter
Lifileucel treatment is like rolling the dice.
Median duration of response (mDOR) was still not reached at
median follow-up of 28 mos (DOR range: 2.2-35.2 mos). No new safety risks have been identified for lifileucel during the long-term follow-up.Exploratory analyses of product-specific characteristics,
including levels of phenotypic markers of T-cell lineage, memory subset, youth, activation/exhaustion, or trafficking did not demonstrate association with response.
ADXS selling point is that listeria can carry large payload compared to virus + PAMP. Do you have a poster that shows how this OV can do so much?
I doubt any OV can accomplish so much.
Looking at STING, listeria .... Repolarising M2's into M1's stories have been all talk and no action. Which population of cells in TME will make the growth factor?
This reminded me of antisense many many years ago.
I thought Flt3 ligand is a growth factor to increase M1 count. I am clueless what Turnstone is doing.
I guess they need a backup plan. OV has been around for many years. Exhausted immune systems need outside helps to counter tumors is my current belief. Number of targets, T cells proportions and quantities all matter.
KEYTRUDA The cost of 20% OS benefit = hyperprogression + delayed irAEs + irAEs
118 patients had delayed irAEs; these were often high grade (39% G3+) including two delayed irAE-related deaths
https://www.annalsofoncology.org/article/S0923-7534(21)01101-7/fulltext
An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumours
https://www.nature.com/articles/s41586-021-03363-z?utm_source=twitter&utm_medium=social&utm_content=organic&utm_campaign=NRRJ_2_SJB_nrclinonc_editorial_socialposts
CDX301 before gnca011 + CDX1140 + RT on liver would be my dream team to treat stage 3/4 cancers
https://clinicaltrials.gov/ct2/show/NCT04536077?term=cdx+301&recrs=ab&draw=2&rank=1
If listeria couldn't flip M2 in TME, I doubt anything will. The futility demonstrated over the years tells me most of these bios are created for Wall St. traders.
Inhibgen => liver metastasis => low CD8+ T-cell count
liver metastatic patients with melanoma or NSCLC
that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8+ T-cell infiltration
The CD8+ T-cell count at the invasive margin was also significantly lower in the liver metastasis+ group versus the liver metastasis- group (liver metastases group n = 22, mean count 547±164.8; no
liver metastases group, n=40, mean count 1441±250.7; P < 0.016; Fig. 4B). In the same tumor samples, PD-1 and PD-L1 expression by IHC was not significantly different in the liver metastases+ cohort as compared with the liver metastases- cohort
I have been burnt too many times by therapeutic cancer vaccines over the years. ADXS, CLDX,... etc. I doubt cancer pts. above 60 or treated by stuff like Humira would mount a strong immune response with enough CD8 to counter solid cancers. GEN-09 probably best cancer pts will get.
I don't think neural networks work. I doubt anyone can train the model using conventional wisdom. I believe MOA of anti PD1/PD-L1 is in TDLN, which would explain why so many Combos targeting TME have failed in last few years.
Using the state of the art prediction pipeline and screening process, more than one hundred twenty neoantigens were predicted from 5 type of solid cancers that were validated by characterizing cognate T cells and their close to 200 unique TCRs captured from the blood of the same individual. These validated neoepitopes of 8 to 11 amino acids represent broad HLA class I coverage with >30 alleles to date.
inhibigens =>Bad TILs => hyperprogression
747.6±121.1 / 175.4 copies/ml at 2 months =4.27(PR)
494.3 (±46.2) /124.1 copies/ ml at 2 months = 4(HPD)
Where is atezolizumab MOA?
Patterns of PD-L1 mRNA expression in plasma-derived exosomes at baseline corr to response to atezolizumab + nab-paclitaxel & pts survival
May be the initial PD-L1 baseline in PB indicated the level of $tril M2 expression in the TDLN not TME.
PD-L1 post treatment in PB indicated the growth of tumor TME.
With 3B mkt cap, they can afford to run 300 pts P2/3 with 10 pts. P1. FDA don't care how CEO tries to boost the share price.
I guess you believe in the conventional wisdom that high TMB and neoantigen load go hand in hand. You must have thousands twitter followers
RP1 is another TTi621 targeting APC. Why they don't add CLDX 301 to these trials is beyond me.
I meant LP. You need LP to target Frameshift mutations.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255011/
PACT is not finding many needles in the haystack.
A median of 8.5 distinct neoE-specific T cells (range 5-15) were isolated per patient. Following functional characterization 13 neoTCRs met selection criteria: three patients with 3 TCRs, one with 2 TCRs, and two had a single TCR. The median predicted neoE:HLA affinity of the selected TCRs was 77 nM (range 6.3 - 5866) and the median IFN-g EC50 was 4 ng/mL (range 1-431)
https://www.abstractsonline.com/pp8/#!/9325/presentation/1438
Why PACT is not finding SLP?
These validated neoepitopes of 8 to 11 amino acids represent broad HLA class I coverage with >30 alleles to date.
https://www.abstractsonline.com/pp8/#!/9325/presentation/3398
TIL science
We identified and validated nine high-avidity anti-viral TCRs and five high-avidity anti-tumor TCRs from these seven libraries. We also showed that integrating activation-based screening with dextramer binding is critical for reducing the false positive rate and could also be useful for decreasing the false negative rate, differentiating our system from other TCR discovery methods.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224336/
What you get from a 3B company TIL? Not much.
Two of these six patients had
developed melanoma that was unequivocally refractory to the BRAF inhibitor dabrafenib in combination with MEK inhibitor therapy immediately prior to TIL treatment but were continued on dabrafenib, with brief interruptions for tumor harvest and TIL infusion, to prevent the rapid disease progression that often accompanies abrupt dabrafenib discontinuation. Both patients developed durable responses following TIL treatment. One patient, who had also failed prior ipilimumab and PD-1 blockade, achieved a PR that lasted approximately 14 months from TIL infusion during which time dabrafenib was continued. The second patient was treated with dabrafenib for approximately three months following TIL infusion, at which point the dabrafenib was stopped. This patient achieved a PR at approximately 12 months after TIL infusion that converted to a durable CR that was ongoing for over four years after TIL infusion at the time of data cutoff
https://ir.instilbio.com/static-files/4f0c5d8d-fa28-4402-9f3b-eaacf92f5db3
Laughing all the way to the bank. Good luck!!
Anther failure targeting TME
ILLUMINATE-301 Key Findings:
Patients in the study were randomized and treated either with 8 mg of tilsotolimod in combination with ipilimumab or with ipilimumab alone. Topline results include:
ORR of 8.8% for the combination arm and 8.6% for ipilimumab alone.
Disease control rate (DCR, defined as stable disease or better) of 34.5% for the combination and 27.2% for ipilimumab alone.
Treatment-emergent adverse events (TEAEs) (Grade 3 and above) occurred in 61.1% of patients who received the combination vs. 55.1% of patients who received ipilimumab alone. Immune-related TEAEs (Grade 3 and above) were reported in 37.6% vs. 30.1%, respectively.
http://www.globenewswire.com/news-release/2021/03/18/2195815/0/en/Idera-Pharmaceuticals-Announces-Results-From-ILLUMINATE-301-Trial-of-Tilsotolimod-Ipilimumab-in-anti-PD-1-Refractory-Advanced-Melanoma.html
TRIL has wasted too much time, even CRIS has developed a combo CA-4948 + ibrutinib to treat Relapsed or Refractory Hematologic Malignancies.
CD-47 space is a big leaking bubble.
https://www.prnewswire.com/news-releases/curis-doses-first-patient-in-phase-1-study-of-ca-4948-in-combination-with-ibrutinib-in-patients-with-relapsed-or-refractory-hematologic-malignancies-301224625.html
There is no need for PD-L1 with plenty of inhibgens expressed.
Median OS in patients with CTCneg was 2.2 months, 95% CI 0.8 – 3.6 (reference), vs 3.7 months, 95% CI 0.1 – 7.5 (HR 0.33; 95% CI 0.13 - 0.83, p 0.019) in patients with CTCpos vs 16.0 months, 95% CI 2.2 – 29.8 (HR 0.17; 95% CI 0.06 - 0.45, p < 0.001) in patients with CTCnull. No correlation was found between PD-L1 expression on CTCs and on tumor tissue. CTC number was correlated with BTS.
https://www.clinical-lung-cancer.com/article/S1525-7304(21)00057-7/fulltext
The proportion of ATLAS-identified
inhibitory to stimulatory responses may be
a predictive biomarker for clinical
outcome. The proportion of ATLAS
identified inhibitory (X-axis) to stimulatory
(Y-axis) neoantigens for the six patients
enrolled in GEN-009-101 are shown, with
diameter of the circle representing tumor
mutational burden. Five patients have not
progressed (grey circles) to date. One
patient progressed prior to vaccination
(burgundy circle). Four additional patients
from a non-vaccinated research cohort have
progressed while on checkpoint blockade
(burgundy circles labeled A). Each patient
from the research cohort had a PD-L1 score
greater than 50% as determined by the
percentage of tumor cells that express PDL1 on the surface by immunohistochemistry
(clone: E1L3N).
Anti PD-L1 and Anti-CD47 should be a killer combo if you believe the conventional wisdom. Why Anti PD-L1 would cause hyperprogression if it targets TME? I think many combos targeting TME have failed because the elephant is the CD4+(inhibigen) in TDLN.
How many bios have a viable treatment for DLBCL? I wonder if GILD would pay $6B for CD47 today.