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dr_lowenstein,
How credible are ONCS mgt. and IP?
Intratumoral injection of ipilimumab and interleukin-2, patients might as well sleep in the doctor's office for the 26 shots in 8 weeks.
A single lesion (0.5-2.0 cm) in each patient was treated with IL-2 (3 mIU) IT TIW x 2 weeks, then BIW x 6 weeks, with escalating doses of Ipi IT weekly x 8 wks. A minimum of 3 patients were enrolled at each dose level. Endpoints included safety, tumor responses, and changes in systemic T cells. Results: 12 patients were treated at 3 Ipi dose levels (0.5, 1, 2 mg). Treatments were well tolerated. The only grade 3 toxicity observed was injection/tumor site ulceration/necrosis, not a DLT per protocol. Other toxicities were grade 1 in nature. An abscopal effect (response in at least 1 non-injected lesion) was seen in 9/12 patients (75%). 10 patients were evaluable for response by immune-related response criteria: 4 PR (40%) and 6 PD. 1 PD was later found to be a CR by resection. The 2 nonevaluable patients had regression of multiple skin lesions.
Do you have the results from OMS-I120 - Phase II Cutaneous T-Cell Lymphoma Clinical Trial?
For patients with high TILs after IL12, they should get into this Atezolizumab trial.
https://clinicaltrials.gov/ct2/show/NCT02425891?term=NCT02425891&rank=1
Will the TNBC patients get Pembrolizumab if their TILs pops after pIL12 ?
Intratumoral plasmid IL-12 electroporation (IT-pIL12-EP) will be administered to approximately 10 patients with triple negative breast cancer (TNBC) with cutaneous or subcutaneous disease. Patients will receive one complete cycle of therapy, consisting of local injection of plasmid IL-12 (pIL-12) followed immediately by electroporation (EP), into accessible tumor lesions. IT-pIL12-EP will be administered in Days 1, 5, and 8 of the single 28-day cycle.
Are TAMs actually hybrids and how anti-CD47 deal with them?
Fusion between cancer cells and macrophages
http://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1935-0
anti-CD47 + IL-12 combo??
IL-12 treatment in vivo alters the functional profile of TIM and TAM
http://www.jimmunol.org/content/178/3/1357.long
MCSF-polarized M2 macrophages as well as CSC-conditioned
M2-like macrophages were able to phagocytose PDAC
cells treated with anti-CD47 mAbs highlights the potential of M2
macrophages, the predominant macrophage subtype present with
the PDAC tumor microenvironment, as biologic tools to target
CSCs and their more differentiated non-CSCs progenies.
tumors in mice treated with both Abraxane and anti-CD47 mAbs
diminished in size, such that one tumor was completely eliminated,
and the remaining tumors failed to relapse
http://clincancerres.aacrjournals.org/content/21/10/2325.abstract
The role of interleukin-12 on modulating myeloid-derived suppressor cells
http://www.ncbi.nlm.nih.gov/pubmed/21453419
400K block @ $1.80
IL12 + PD1/PDL1 inhibitor
Patients who received IT-pIL12-EP and later went on to receive a PD1/PDL1
inhibitor demonstrated a high PD1/PDL1-associated response rate (n=14; 64%
BORR), and those who did not have an intervening therapy had a BORR of
75% (n=8)
http://finance.yahoo.com/news/oncosec-presents-positive-melanoma-clinical-204500361.html
ARQ761 in combination with anti-CTLA4 or anti-PD-L1???
IPI-549, a potent and selective inhibitor of PI3K-gamma.
In preclinical models, treatment with IPI-549 leads to a decrease in tumor-associated immune suppressive myeloid cells. IPI-549 treatment also leads to a decrease in FOXP3 T-regulatory cells, which have immune-suppressive effects, and an increase in intratumoral CD8+ T-cells, which are known to play a role in inhibiting tumor growth.
http://finance.yahoo.com/news/ipi-549-alters-immune-suppressive-120000430.html
This implied MTD was found earlier than expected and no PR in solid tumors. Nothing earth shattering seen in P1 IMO.
Pac-Man at Stanford, why P1 stopped at 20??
CD47 clinical trial is small and is not currently recruiting additional patients. As the trial progresses, information about the patients in the trial and the data about how the antibody is performing are kept confidential.
We have over 20 patients enrolled, we have a solid tumor study and an acute myeloid leukemia underway, so we have two different Phase 1’s up and running. They will finish later this year.
http://wxpress.wuxiapptec.com/next-generation-immuno-oncology-creating-new-pathway-eat-cancer-chat-jonathan-macquitty-ceo-forty-seven/
anti-CSF-1R (c-fms) antibody
Of the 21 pts evaluable by central read, 8 (38%) pts had a best overall response of stable disease, including 1 pt with a 20% reduction in tumor burden (0.5 mg/kg, non-small cell lung cancer). Of the 25 pts evaluable by local read, 1 (4%) pt had a partial response with a 40% reduction in tumor burden (10 mg/kg, paraganglioma with liver metastasis), and 6 (24%) pts had stable disease.
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=4017&sKey=7b157eb4-b4d8-4da2-8c63-8be2af3a5f37&cKey=7d51e9ad-6c77-498d-8bb6-fd3ac5bf152a&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267
Ox40
Eleven of 70 pts (16%) have been treated with MOXR0916 for > 6 months (≥9 cycles) with a best response of stable disease per RECIST v1.1
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=4017&sKey=b01a929a-449c-4fd7-89e5-7dc10238925f&cKey=39e0a216-850a-43fc-ab54-0727214f8117&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267
combination of a FGFR inhibitor with an AKT inhibitor has a profound potential to treat PCa
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=06d5b018-96fb-47fa-9614-ffb650401284&cKey=1f4b4ad9-2186-4d40-a20f-d9c9da83c76d&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267
PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients
There were 10 RECIST complete or partial responses (CR/PR) out of 37 (15 BRCA m) evaluable pts, including gBRCA m breast (n=4), platinum-resistant gBRCA m ovarian (n=2), BRCA wildtype (WT) triple negative breast (n=1), BRCA WT ovarian (n=2) and BRCA unknown prostate (n=1) cancer pts.
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=4017&sKey=946fbd6f-3560-4ea2-aed6-7788155ea81b&cKey=fbf921a7-552a-44ee-aa04-a345ece10ad8&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267
TRIL Will anti-CD47 work on cancer cell/macrophage hybrids?
http://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1935-0
Fusion between cancer cells and macrophages
http://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1935-0
From 10K:
Under the terms of our credit facility, Hercules could accelerate our payment obligations upon the occurrence of a circumstance that would reasonably be expected to have a material adverse effect, as defined in the credit agreement, or another event of default. If our principal obligations under such credit facility (which totaled approximately $15.0 million as of December 31, 2015) are accelerated, we would need to secure additional financing to fund our operating expense and capital expenditure requirements as early as the middle of April 2016. In the event we are unable to secure the necessary financing, we may need to cease operations or file for bankruptcy protection.
CD163/CD68 ratio (an indicator of M2 polarisation) was significantly (P<0.05) higher in tumour resection specimens than in biopsies
The biopsy-induced tissue trauma might explain the observed shift in macrophage polarisation towards the tumour-promoting M2 type and could lead to accelerated tumour progression.
http://www.nature.com/bjc/journal/v113/n3/full/bjc2015212a.html
Close-up of pancreatic cancer cells, why the smaller TTi-621 will do better job than mAb is obvious.
http://www.cancerresearchuk.org/about-us/cancer-news/news-report/2016-04-06-immunotherapy-and-chemo-combination-shows-early-promise-for-pancreatic-cancer
13G filings
Franklin Resources, Inc. 395,000 5.1%
Point72 Asset Management, L.P. 198,600
Ridgeback Capital Investments L.P. 370,537
Baker Bros. Advisors LP 413,697
James H. Stebbins 338,739
Opaleye Management Inc 210,000
Merlin Biomed 443,631
Deerfield 172,307
Thomas D. Mottola 621,749
Janus Capital 552,378
Short interest down almost 1 million from 12/1
3/15/2016 3,379,406
combinations will dominate treatment strategies, probably starting with combinations of immune therapies, followed by, if ineffective, immune therapies with VEGF receptor inhibitors
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771089/pdf/ptj4103185.pdf
microglia acts like TAM
C1q is actually just the first in a series of proteins that accumulate on synapses marked for elimination. Stevens has begun to uncover evidence that there is a wide array of protective “don’t eat me” molecules too. It’s the balance between all these cues that regulates whether microglia are summoned to destroy synapses. Problems in any one could, conceivably, mess up the system.
microglia are doing and what causes them to do it. These cells, it turns out, appear in the mouse embryo at day eight, before any other brain cell, which suggests they might help guide the rest of brain development—and could contribute to any number of neurodevelopmental diseases when they go wrong.
https://www.technologyreview.com/s/601137/the-rogue-immune-cells-that-wreck-the-brain/
TAM and breast cancer
macrophage co-culture with apoptotic MCF-7 cells yields a conditioned media that not only promotes tumor growth in vivo, but also increases metastatic ability of the MCF-7 cells, whereas conditioned media from a macrophage culture alone inhibits tumor metastasis in vivo.
http://www.mdpi.com/1422-0067/16/6/11966/htm
MCSF-polarized M2 macrophages as well as CSC-conditioned
M2-like macrophages were able to phagocytose PDAC
cells treated with anti-CD47 mAbs highlights the potential of M2
macrophages, the predominant macrophage subtype present with
the PDAC tumor microenvironment, as biologic tools to target
CSCs and their more differentiated non-CSCs progenies.
.. tumors with their dense stroma may represent too
strong a barrier for the CD47 antibodies to reach the cancer
cells
..tumors in mice treated with both Abraxane and anti-CD47 mAbs
diminished in size, such that one tumor was completely eliminated,
and the remaining tumors failed to relapse
http://clincancerres.aacrjournals.org/content/21/10/2325.abstract
TAMs facilitate almost every step of the metastatic cascade, from initial migration to intravasation, dissemination, extravasation, and establishment of metastasis at secondary sites
http://www.hindawi.com/journals/mi/2016/9012369/
combination of immunotherapy and radiation therapy
Current data shows that three patients have had an ongoing complete response to therapy, which suggests that the combination of immunotherapy plus radiation can be extremely effective in a subset of patients.
https://www.astro.org/News-and-Media/News-Releases/2015/Hiniker_AM15.aspx
PC and immune therapies
there are pathologic changes from the classic prostate adenocarcinoma to a neuroendocrine or anaplastic PC, a phenotype with little or no dependence on the androgen receptor pathway.
visceral disease scenario several cytokines mediate systemic immunosuppression. Immune treatments in this setting may be unable to counteract the established cancer-related immune system dysregulation. Timing of immune therapies may play a key role for treatment efficacy.
- See more at: http://www.cancernetwork.com/oncology-journal/visceral-metastases-prostate-cancer-underestimated-and-understudied-subgroup#sthash.ibE0Sh2l.dpuf
Cabozantinib is a potent targeted therapy that inhibits MET
Partial bone scan resolution in 4 of 10 evaluable patients, no CD47 status
http://www.exelixis.com/sites/default/files/Winer_MBC_ASCO%202012_FINAL_poster_535.pdf
Expression of mouse CD47 on human cancer cells profoundly increases tumor metastasis in murine models
mCD47-expressing PC-3 cells subcutaneously implanted in NSG and CB17. Scid
mice metastasized to the sentinel lymph node, lung and liver significantly more efficiently than the control cells.
When implanted orthotopically to NOD. Scid mice, these cells spontaneously metastasized to lung and liver
http://link.springer.com/article/10.1186%2Fs12885-015-1980-8#/page-1
CD47 / MET strongly associated with lymph node metastasis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226673/
CD47 and pancreatic neuroendocrine tumors
http://www.pnas.org/content/early/2016/03/30/1600007113
CC-90002 – exploring optimization of CD47 target promise: Dr. Daniel pointed to preclinical data for this ph.I anti-CD47 antibody demonstrating some of the best tumor responses they have seen, and the company seems determined to capitalize on the congruence of its macrophage-related mechanism to more traditional T-cell IO approaches. It does seem like some additional work is still to be done; while they seemed confident the antibody construct would avoid hemagglutination, a side effect we note has been limiting for the target, they did highlight the need for continued ph.I work to better understand the complexity within tissue distribution and pharmacologic effect (in particular the thrombospondin ligand for the target), as well as the immune mechanism. AML seems to be the initial path forward, with the company submitting a plan to the FDA for this indication, and the company seemed determined to tackle some of the fundamental challenges with ‘90002 or follow-on antibodies.
http://www.investorvillage.com/smbd.asp?mb=341&mn=201733&pt=msg&mid=15519402
CD47 and infections
Several viruses encode cell surface proteins similar to CD47 that enable infected cells to evade host immunity by engaging SIRPa [13]. Similarly, elevated CD47 expression by some cancers protects them against natural killer (NK) cells, macrophage clearance, and antibody-dependent tumor cell killing
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128220
CD47 regulates the phagocytic clearance and replication of the Plasmodium yoelii malaria parasite
http://www.pnas.org/content/112/10/3062.full
HIGH EFFICACY OF ABT-493 AND ABT-530 IN HCV GENOTYPE 1 INFECTED PATIENTS WHO HAVE FAILED DAA regimens
Arm A enrolment was stopped early to investigate higher doses of study drugs in other arms. Among patients with SVR12 data, SVR12 was achieved in 6/6 (100%) Arm A patients, 20/21 (95%) Arm B patients, and 19/20 (95%) Arm C patients. Two virologic failure swere observed; 1 relapse in a nArm Bpatient with baseline NS5A RAVs, and 1 breakthrough at treatment week 8 in Arm C
in a patient with Crohn’s disease on immune suppressant therapy