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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?
Fate
The ongoing Phase 1 clinical trial in relapsed / refractory B-cell lymphoma is assessing FT516 in an off-the-shelf treatment regimen of up to two cycles, with each cycle consisting of three days of conditioning chemotherapy (500 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine), a single-dose of rituximab (375 mg/m2), and three weekly doses of FT516 each with IL-2 cytokine support. The FT516 treatment regimen is designed to be administered in the outpatient setting.
https://www.globenewswire.com/news-release/2021/06/04/2241947/24675/en/Fate-Therapeutics-Highlights-Positive-Interim-Data-from-its-Phase-1-Study-of-FT516-in-Combination-with-Rituximab-for-B-cell-Lymphoma-at-2021-ASCO-Annual-Meeting.html
Breyanzi, a CD19-directed CAR T cell therapy, was approved by the U.S. Food and Drug Administration (FDA) in February 2021 for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B
https://www.businesswire.com/news/home/20210610005259/en
Breakthrough is LAGing from BMS
https://s21.q4cdn.com/104148044/files/doc_presentations/2021/ASCO-Investor-Presentation.pdf
A final issue is how best to approach cancers that carry HLA class II-restricted public neoantigens. Immunologic responses have been achieved using adoptive transfer of CD4+ T cells that recognize class II-restricted neoantigens144,145. Additionally, neoantigen vaccines that have demonstrated enhanced anti-tumor immunity have been associated predominantly with CD4+ T cell responses146–148. The precise mechanisms of these CD4+ T cells in mediating anti-cancer activity remain to be determined100,149,150, although augmenting activation of cytotoxic T cells and inducing tumoricidal inflammatory macrophages are two established functions of tumor antigen-specific CD4+ cells. Directly cytotoxic HLA class II-dependent CD4+ T cells have also been observed
https://www.nature.com/articles/s43018-021-00210-y.epdf?sharing_token=n3kcQEUfV_RpFkasmwgg-dRgN0jAjWel9jnR3ZoTv0O6LxEJm8a4Q-1-XD3cU2cm9QKr0iASAdo-nehe2WHUbg6IT1xA44nfTDIV_kqcITaQxqXUel7mfaCnpke_s85iEAZ10-7bYELoC3XnHYgT8C0s6riz-5xZRjuE8CBh4os%3D
From IOVA:
Appropriate amount of TIL was manufactured
from tumors regardless of location of resection
Target lesion SOD reductions were seen across
the range of TIL total cell dose
For each 6-month decrease in exposure to prior anti–PD-1 / anti–PD-L1, the median DOR to lifileucel will be nearly doubled.
GEN011 is the Coley's ACT to treat cancers.
So Lyell is the CAR-T version of Archilles.
If inhibigens work as GNCA described, Lyell CAR-T TILs = IOVC TILs.
TILs target a variety of tumor antigens, but it is thought that the clinical efficacy of TILs is largely driven by specific recognition of mutated tumor neoantigens. Further, broad TIL efficacy has been limited by poor enrichment of tumor-reactive T cells, poor quality and growth potential of expanded T cells, and failure to maintain polyclonality of TILs during production. We have designed LYL845 to incorporate our Epi-R technology that has shown promising improvements in enhancing T cell potency, antitumor activity and increased polyclonality of TILs. We expect to submit an IND to test LYL845 in multiple solid tumor indications in the second half of 2022.
Inhibigen v. c-Jun. Inhibigen is turning into the predictor for anti-PD1 efficacy and HPD.
>>anti-ROR-1 CAR-T<<
These CAR-T ACTs need to see the targets. A half blind man swinging a big hammer not going to work. Immune escape is the cause of cancer in the first place.
B cells and associated antibody responses play an important role in acute SARS-CoV-2 infection, and CD8 T cell responses that are normally sufficient might no longer be adequate in the setting of compromised humoral immunity. This is consistent with published data demonstrating that uncoordinated immune responses in the elderly was associated with severe disease and poor outcomes
These results are compatible with a model in which CXCR3-high blood-circulating EM cells are recruited in the tumor, irrespectively of their antigen specificity. Then, rare tumor-specific TOX-low EM TILs driven by persistent antigenic stimulation differentiate into TOX-high XCL1-high quiescent (Tpex) cells which, following interaction with XCR1+ APCs, give rise to highly proliferative terminally exhausted/dysfunctional (Tex) CD8+ TILs that engage in tumor cell killing
https://www.nature.com/articles/s41467-021-23324-4
IS Lyell better than DAC?
Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming
https://www.nature.com/articles/s41467-020-20696-x?elqTrackId=31b379fbd9d04fbd89c32628a9acc6df
We did not detect S-reactive T cells in the periphery, and a direct mechanism for T cells driving CRS in this case could not be demonstrated. However, vaccine-activated T cells that contributed to CRS could be resident within tissue or lymph nodes and, therefore, undetectable in the blood15. T cell cross-reactivity, as a result of sequence similarity between spike protein and tumor neoantigens, is an alternative, although less likely, cause of CRS in this case. Cross-reactivity to cardiac tissue was reported as a mechanism of ICI-related myocarditis16, and this patient’s history of irAEs and the high neoantigen load (typical of MMRd CRC)17 could, in theory, increase the likelihood of T cell cross-reactivity
https://www.nature.com/articles/s41591-021-01386-7?utm_source=twitter&utm_medium=social&utm_content=organic&utm_campaign=NRRJ_2_SJB_nrclinonc_editorial_socialposts
From Achilles
Median dose of
15 x 106 cNeT
in initial 6 patients
Tumor reduction in 2 of 4 lesions of approx. 55%
and 90% in patient that received the highest cell dose
• Evidence of engraftment in 3 of 6 patients, with
highest dose associated with highest engraftment
• Ability to characterize infused cells at level of
individual cNeT reactivities, in contrast to standard
TIL
– Basis for potency assay
– Documented polyclonality of infused products and
engrafted cells (up to 28 reactivitie
Manufacture of cNeT from
blood and other sources
As of 10-May-2019, 33 patients received mRNA-4157 alone or in combination. No DLTs or related SAEs or AEs ≥ grade 3 were reported. Of the 13 patients treated with monotherapy (3 melanoma, 8 NSCLC, 2 MSI-high CRC), 11 patients remain disease free on study, median follow-up of 10 months. Of the 20 patients treated in combination (1 TMB-high metastatic cutaneous squamous cell, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high (CRC, prostate, endometrial), 13 had received prior CPI, 5 PRs (2 in patients previously treated with PD-1/L1 inhibitors), 6 SD, and 8 PD were reported. Neoantigen specific CD8+ T-cell responses have been detected.
https://meetinglibrary.asco.org/record/179438/abstract
TILs are exhausted because there are too many bystanders as DC are disabled by soluble PDL1 in TDLN. ACT containing billions Tscm CD4/CD8 targeting neoantigens will solve both issues.
Only 1/12 pt. with no PD-L1 achieved PR.
The combination of SNS-301 and pembrolizumab:
67% (n=8/12) of patients achieved stable disease (SD) or partial response (PR), including:
One patient with PD-L1 negative tumor who achieved a tumor reduction of 71% that is still ongoing after 11 months of therapy. Nanostring™ data for this patient show T-cell increase and T-cell activation.
Seven patients achieved SD, including two patients with long-standing SD (8 and 10 months).
Bispecific mAb worked well in mouse models and cell lines too. Malfunctional immune system has shown conventional wisdom is a failure.
Too many bystander T cells when DC in TDLN not working. CD47
the majority of human TILs do not display features of exhaustion or tumor-reactivity, and are clonally disconnected from the exhausted TILs, suggesting that most of them are not tumor specific; and that (ii) tumor-specific exhausted/dysfunctional CD8+ TILs can co-exist with two rare, quiescent precursor subtypes: an exhausted TOX+ PD1+ TIM3- XCL1+ (Tpex) state; and a pre-exhausted/dysfunctional (EM) state with low expression of TOX and inhibitory receptors, and high expression of CXCR3 and GZMK, that resemble blood circulating EM cells. The proposed CD8+ TIL differentiation model based on these observations has important implications for the design of therapies aimed at preventing T cell exhaustion, and for the identification of tumor-specific T cells with high stemness for their use in adoptive cell therapies62.
We observed a distinct separation between CD4+ and CD8+ T cells, which could be further divided into subgroups. In particular, we identified a cluster of naive-like CD8+ T cells (which may consist of naive as well as central memory cells) and a smaller cluster of naive-like CD4+ T cells
https://media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41467-021-23324-4/MediaObjects/41467_2021_23324_Fig1_HTML.png?as=webp
Immunotherapies CPI, vaccines need a bunch of functional lymph nodes. Adding the Tscm act data from PSTX, GEN011 should not disappoint.
Have they compared 2 single CARs to dual CAR?
We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre
There is plenty of room for improvements. IOVA TIL ACT doesn't target neoantigens so immune escape still big issue. Why GNCA hired their former VP operation?
I lost track of how many mAbs targeting PSMA have gone thru the clinics. PGNX bet the whole company on it.
https://www.businesswire.com/news/home/20110217006989/en/Progenics-Reports-Positive-Preliminary-Data-from-Ongoing-Phase-1-Clinical-Study-of-PSMA-ADC
IOVA bar
Sixty-six patients received a mean of 3.3 prior therapies (anti–programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti–PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively.
PSTX has High-Quality Shareholder Base, low quality targets
GNCA has low-Quality Shareholder Base, high quality targets
From Poseida PSTX:
Products with High % of TSCM Cells:
• Strong correlation with best responses in the clinic
• More gradual tumor killing with less toxicity
• Better duration of response and potential for re-response
https://investors.poseida.com/static-files/49ba1622-3013-4ac5-90dd-58119c2ed2cd
Looks like GEN11 without ATLAS. BNT can afford the best and fastest processes to minimize the ACT wait time.
That is what GNCA saying in 2021.
So this seems to suggest that a number of mutations go undetected when a patient's T-cells are screened. If the data is confirmed by others that would mean not only the frequency of neoantigens has been underestimated, but many 'cold' types are likely to be more immunogenic than thought
More evidence high PDL1, TMB mean nothing
high TMB is not predictive of a response in a tumour-agnostic manner among patients receiving ipilimumab+nivolumab for advanced stage rare solid tumours
Analysis from the phase II CA209-538 study suggesting that a high TMB is not predictive of a response in a tumour-agnostic manner among patients receiving ipilimumab+nivolumab for advanced stage rare solid tumours: https://t.co/4vWyEDBEDp #ImmunoOnc
— NatureRevClinOncol (@NatRevClinOncol) May 6, 2021
combination of cyclophosphamide and interleukin-2 allows CD4+ T cells converted to Tregs to control scurfy syndrome
https://ashpublications.org/blood/article-abstract/137/17/2326/475193/A-combination-of-cyclophosphamide-and-interleukin?redirectedFrom=fulltext
IF this combo works better than the PDL1 bispecific, it is another blow to conventional wisdom.
GSK had high hopes in 2019 that Merck KGaA’s bintrafusp alfa could be a substantial addition to a pipeline that was in need of attention, paying more than $4.2 billion for the cancer immunotherapy in early 2019.
GSK secured co-development and co-marketing rights to the bifunction fusion protein, an anti-PD-L1/TGF beta trap for solid tumours including lung cancer.
GNCA should have tried GEN009 on pancreatic cancer or other with low 5 yr. OS.