This CART not much better than ADXS vaccine

interim results from its Phase 1 clinical trial of P-PSMA-101, the Company's solid tumor autologous CAR-T product candidate to treat patients with metastatic castrate-resistant prostate cancer (mCRPC).

10/14 (71%) patients demonstrated measurable declines in PSA levels
5/14 (36%) patients showed a decline in PSA levels of 50% or more
One patient demonstrated evidence of complete tumor elimination and remains in a durable response of greater than ten months at the time of this presentation

https://www.prnewswire.com/news-releases/poseida-therapeutics-to-present-interim-results-from-phase-1-trial-of-p-psma-101-at-asco-genitourinary-cancers-symposium-301484390.html

Wainwright analyst making min wage. Leerink max. TIL KOLs as good as PD1/TMB KOLs

Shock and awe TME as in lymphodepletion will be required too.

Counting numerous failures targeting TME, I think night vision + fresh troops is required to beat cancers.

13G, GSK 9.9%

Lymphodepletion, known to transiently reduce the frequency of Treg cells, improves persistence of CAR-T cells as well as therapeutic outcome

https://www.frontiersin.org/articles/10.3389/fonc.2019.00279/full

16/19 patients in Titan compared to 6/42 NIH. If inhibigen beats TMB in 2022, a lot of TIL bios will be written off.

CLDX combo:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844797/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102435/

decitabine was in cldx combo too. Which biologic/vaccine targeting CEA has yielded great ORR and DOR?

Trading volume dropped 80% since GNCA updated it's most wanted list.

In order to increase the number of antigen-specific T cells to >500 million cells, rapid expansion protocols were tested. T cells were cultured for 12 days with low-dose IL-2 and two different non-specific stimuli: either anti-CD3 and CD28 monoclonal antibodies (T Cell TransACT, Miltenyi Biotec), or anti-CD3, CD28, and CD2 monoclonal antibodies (ImmunoCult, StemCell Technologies) for 12 days. Fold expansion and percent viability of the two cultures were determined. Culturing T cells in GRex 100M flasks generated greater than 350-fold expansion with high (>90%) viability after 12 days (FIG. 12), irrespective of the source of the antibodies or delivery technology (ImmunoCult or T Cell TransACT). The addition of different combinations of cytokines (IL-2, IL-7, IL-15 and IL-21) were also tested (FIG. 13, Panel A) to determine the conditions that result in increased expansion of central memory T cells without inducing increased exhausted or terminal effector memory T cells. Media containing low and high-dose IL-2 alone resulted in significantly lower expansion than the other cytokine-containing media (FIG. 13, Panel B). Low-dose IL-2 resulted in a lower frequency of central memory CD4+ and CD8+ T cells than the other media (FIG. 13, Panels C and D, respectively, for CD4+ and CD8+). A central memory phenotype (CM) is identified as CCR7 high and CD45RA low; effector memory (EM) phenotype is CD45RA low and CCR7 low; effector memory re expressing CD45RA (TEMRA) is CD45RA high and CCR7 negative. Medium containing IL-7/IL-15/IL-21 (Medium 4) yielded the highest mean fold expansions and acceptable memory phenotype and therefore was selected for the rapid expansion protocol yielding exemplary autologous cell therapy compositions (GEN-011).

The cryopreserved T cells were thawed, the cryoprotectant was removed via medium exchange, and the cells were resuspended in serum-free T cell culture medium (OpTmizer, containing Immune Cell SR; Gibco). Cells were co-cultured with the above-prepared MDDCs and the same patient-specific OLP pool at 2 pg/mL per OLP (range: 0.5-10 pg/mL) in a G-Rex or equivalent tissue culture vessel for up to 10 ± 2 days in a 37°C incubator containing 5% CO2. A MDDC to T cell ratio of 1 :8 ± 4 during the antigen-specific stimulation and expansion culture period was employed. The medium was supplemented every 2-3 days with combinations of cytokines, including but not limited to 12.5 IU/mL IL-2 (range: 8-20 IU/mL), 5 ng/mL IL-7 (range: 1-20 ng/mL), 1 ng/mL IL-15 (range: 1-20 ng/mL), and 1 ng/mL IL-21 (range: 1-20 ng/mL).

Hasn't worked in 145 studies. I thought CLDX combo had a chance. Antigen shedding will keep DOR short

DOR = 31.0 wks for this study
(13 to 72)
https://clinicaltrials.gov/ct2/show/results/NCT01343043?term=NY-ESO-1&draw=2&rank=3

Cassian Yee’s talk was focused on three key aspects that define the efficacy of cellular therapies using peripheral antigen-specific T cell clones; persistence, antigen spread, and tumor microenvironment (TME) modulation. First in a trial in which patients were treated with NY-ESO-1-reactive CD4+ T cell clones without prior lymphodepletion, and then in a trial with gp100 in melanoma patients, patients with a complete response had long-term persistence of CD8+ T cells, while patients with progressive disease had very short-term persistence. Persisting cells had a central memory (Tcm) phenotype. Yee and colleagues found that when cells were treated with IL-21 during the priming phase, antigen-stimulated naive T cells would upregulate CD28 and CD127, suggestive of the Tcm phenotype. In a trial in patients with AML, WT1-specific T cells primed with IL-21 during culture led to Tcm cells that would persist and were associated with a durable clinical response

Warrant holders stopped selling. They understand 100 is more than 1

ADXS also found numerous frame shift mutations common on tumor types, which resulted in long peptides in their HOT vaccine. Are clonal neoantigens same as frame shift mutations?

I am the only person listening to Chip?

Computer prediction has not worked for ADXS and many other bios

I grabbed a few billion stem like T cells on fire sale.

A billion stem like t cells is a tsunami for any tumor.

011 showed activity in a melanoma pt.

Looking at sitc poster, 2 pts were dosed at about 50 mil and 200 mil. cells. PELEUS seems to be the bigger issue even if the updated process can boost the dosage.

How many LVS longs know VIP junkets have $billions deposit and little accounting. Sands will face $billions claims from junket accounts

ACHL is making progress while GNCA is running out of breath.

a fusion of IL-2v to a high-affinity anti-PD-1 antibody was prepared to bring the IL-2v to the surface of PD-1-expressing cells and enhance stimulation. The novel PD-1-targeted IL-2v fusion immunocytokine dramatically increased IL-2R signaling and was shown to bind in cis to PD-1+ TIL, delivering IL-2v to TIL that were potentially enriched for tumor specificity. In an aggressive orthotopic pancreatic cancer mouse model, this construct had a tumor eradication and survival benefit over FAP-IL2v combined with anti-PD-1. It led to a significant specific tumoral expansion of PD-1highgranzyme B+ highly active CD8+ effectors, while not affecting peripheral T cells. The human variant was found to be superior over anti-PD-1 and IL-2 combination treatment, and its efficacy could be enhanced by combining it with anti-PD-L1 or anti-cancer vaccines.

https://acir.org/weekly-digests/2020/november/sitc-2020-35th-anniversary-annual-meeting

I wish cold tumor types were included in Titan-1

There is no liquidity. I bought 2K shares and the price jumped 75 cents.

The goals of TL4 agonist and systemically mAbs are antigen presentation, induce stem like T cell and block exhaustion. GEN011/ planet seem to have these covered ex vivo with TIL precursor.

GNCA has a TCR program with U of minnesota targeting a hot neoantigen found in pancreatic cancer pts.

Parallel high-dimensional analysis delineated five distinct antigen-specific tissue-resident memory T (Trm) cell populations. Intratumoral and intrahepatic HBV-specific T cells were enriched for two Trm cell subsets that were PD-1loTOXlo

https://www.cell.com/immunity/fulltext/S1074-7613(21)00257-0

That is what makes Titan part A interesting. No PD1 or lymphodepletion, just weekly well targeted naive T cells v. suppressive TME.

All 87 patients experienced AEs, with 70 (80%) experiencing grade 3 or higher events (Supplementary Table 4). The most common grade 3 or higher events observed within 1 month after infusion included leukopenia (76%), thrombocytopenia (37%) and pyrexia (33%). A total of 61 patients (70%) had CRS

https://www.nature.com/articles/s41375-021-01345-8

GNCA does not use TIL and gene edit, other bios don't use ATLAS or neoantigens.

Microbial short-chain fatty acids modulate CD8+ T
cell responses and improve adoptive
immunotherapy for cancer

https://www.nature.com/articles/s41467-021-24331-1

GEN011 is replacing Ebo (high CD45RO, EOMES, FAS, CD27, CD28, KLRG1, PD-1, LAG3, and TIM3 expression) which is expanded in the TME of patients with advanced NSCLC, and its expansion is independently associated with reduced efficacy of anti-PD therapy

https://cancerdiscovery.aacrjournals.org/content/11/7/1700

PFS time versus T cell–inflamed GEP score in 244 patients from KEYNOTE-012 and KEYNOTE-028 for the 9 cancer cohorts used to determine the T cell–inflamed GEP.

https://www.jci.org/articles/view/91190

No gene editing required.

In aged mice, accumulation of CD45RB in P1 cells attenuates TCR signaling and limits the formation of the P4 subset. Nakajima et al. showed that this limitation can be overcome by CD45 inhibition or strong antigenic stimulation through the introduction of xenogeneic or allogeneic cells.

https://acir.org/weekly-digests/2021/june/a-fountain-of-youth-for-t-cell-function

Is gnca using peptide-pulsed dendritic cells in Planet?

VELOS manufacturing process
: Tumour and blood
samples undergo genomic analyses to identify clonal neoantigens. In parallel, TIL are expanded
from tumour fragments and monocyte-derived dendritic cells are generated from whole blood.
In the final step, the co-culture of TIL with neoantigen peptide-pulsed dendritic cells drives the
expansion of cNeT

Has anyone tried low dose NK -> CAR T or NK + TIL after lymphodepletion?

Why is Fate applying TIL preconditioning regiment in their P1 solid cancers?