35 replies to this topic

[reason]

All commonalities in cancer are interesting, as part of the high cost of dealing with cancer is based on the many, many different varieties and the great variability of its biochemistry even between individual tumors. Anything that is common between many types of cancer and between tumors offers a possibility of a lower-cost and broader therapy. The cell surface marker CD47 has shown up of late as a possible commonality, and work continues to see whether a therapy can be built on this:

A decade ago, [researchers] discovered that leukemia cells produce higher levels of a protein called CD47 than do healthy cells. CD47 [is] also displayed on healthy blood cells; it's a marker that blocks the immune system from destroying them as they circulate. Cancers take advantage of this flag to trick the immune system into ignoring them. In the past few years, [researchers] showed that blocking CD47 with an antibody cured some cases of lymphomas and leukemias in mice by stimulating the immune system to recognize the cancer cells as invaders. Now, [researchers] have shown that the CD47-blocking antibody may have a far wider impact than just blood cancers.

"What we've shown is that CD47 isn't just important on leukemias and lymphomas. It's on every single human primary tumor that we tested." Moreover, [the scientists] found that cancer cells always had higher levels of CD47 than did healthy cells. How much CD47 a tumor made could predict the survival odds of a patient. To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the CD47 was [blocked], the macrophages engulfed and destroyed cancer cells from all tumor types.

Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment - colon cancers transplanted into the mice shrank to less than one-third of their original size, on average.

Link: http://news.sciencem...all-tumors.html

<br> <br>View the full article

[Logic]

An easy read of the above info why normal cells aren't affected:

http://stanmed.stanf...r/article7.html

Also:
The Other Side of CD47: a Way to Spawn Induced Pluripotent Stem Cells \
http://www.fightagin...-stem-cells.php

So what is this antibody and is it available?
"...Similarly, CD47 ligation rapidly induces apoptosis in B-cell chronic lymphocytic leukemia (CLL) cells. Treatment with a disulfide-linked antibody dimer induces apoptosis of CD47-positive primary B-CLL and leukemic cells..."
http://en.wikipedia.org/wiki/CD47

Edited by Logic, 19 May 2013 - 08:29 PM.

[Logic]

Anti-CD47 antibody [B6H12.2] (ab3283)FOR SALE!
http://www.abcam.com...122-ab3283.html
All antibodies:
http://www.abcam.com...TargetName=CD47

"...solid tumor cells treated with the blocking anti-human CD47 (hCD47)
mAbs B6H12.2 and Bric126 were efficiently phagocytosed by
human and mouse macrophages..."
http://www.pnas.org/...623109.full.pdf

Edited by Logic, 19 May 2013 - 09:09 PM.

[Logic]

C60oo stops cancer from switching off mitochondria so they can send an apoptosis signal???

Switching them on again with a kickstarter such as DCA and then protecting them with C60oo may be the way to go?
http://www.ncbi.nlm....pubmed/22614004
http://www.ncbi.nlm....pubmed/17222789
http://www.cbc.ca/ne...ents-crowe.html

Green Tea, Mebendazole may be effective against cancer by a similar pathway?
"...Mining the compendium for small molecules that boost OXPHOS gene expression and decrease ROS levels
Remarkably, both analytical strategies spotlighted microtubule modulators, including both a microtubule stabilizer (paclitaxel) and several destabilizers (mebendazole, nocodazole, podophyllotoxin, and vinblastine), as agents that boost OXPHOS expression while suppressing ROS levels. The second strategy also yielded deoxysappanone B, a natural product found in sappan wood40, whose molecular mode of action is unknown and has not been previously linked to microtubule biology..."
http://www.ncbi.nlm....les/PMC2715872/


Interestingly CD47 works similarly in that blocking this protein means that cancer cells no longer send a 'dont eat me' signal to your immine system and get eaten by autoghagy. The CD47 blocking antibody is available!
http://www.longecity...therapy-target/

Could C60oo synergise with DCA, Mebendazole, Green Tea, PQQ etc. to keep kickstarted mito's on and thus kill cancer?

[resveratrol_guy]

Good thread! CD47 deserves MUCH more attention than it has been getting here for the past 18 months. To that end:

 

http://stemcell.stanford.edu/CD47

 

says:

 

"(8/15/14) Update on the anti-CD47 cancer therapy clinical trials

The phase-1 clinical trial of the anti-CD47 antibody is designed to test its safety. The trial will accrue one patient per month at very low doses, and the first groups of participants have been identified from among current Stanford Cancer patients. Currently we are not recruiting new patients to this trial.

If enrollments do open up in the future, that information will be posted on this page. When and if enrollments open up, potential inclusion in this phase-1 trial will be based solely on physician referrals. If there are openings for new participants, and if you meet certain requirements, information posted on this page will describe how your physician can submit a request to the clinical trials team to consider your participation.  

Given the limited nature of this safety trial, we urge that patients not delay or forgo recommended treatments in hopes of participating in this research effort."

 

Translation: we're going to go REALLY REALLY SLOW in order to avoid problems with the FDA, and moreover because terminally ill people should not be given the choice to take any risks whatsoever in order to save their lives. How do we tolerate this outrageous paternalistic mentality as a society? But OK, at least there is a trial in the works.

 

And let me guess... antiCD47 antibodies can no longer be patented, so all this research will be thrown in the garbage regardless of the trial outcome. At least, the above "FOR SALE" link still works, and appears to be human-compatible, if I'm reading the specs correctly. Uh... and someone might want to download the molecular topology before it gets banned for being subversive to the pharmocracy.

 

Edited by resveratrol_guy, 12 November 2014 - 02:55 PM.

[jondoeuk]

4 companies and 2 charities so far (the more the better) http://trilliumthera...res-Q2-2015.pdf

[mag1]

I have edited the tags for this thread to include the tag "cancer cure". Even though CD47 drugs have not yet resulted in the publication of human clinical results, the preclinical results justify this  new tag.

 

It will be especially interested to see what synergies emerge when CD47 drugs are combined with other immune drugs (e.g. anti-CTLA-4, anti-PLD1 etc.).

[jondoeuk]

Ludwig Cancer Research and Stanford University in the US should be initiating a Phase I trial in solid tumors. The Oxford Branch of Ludwig will be doing the same this year, but in non-solid tumors. Also at lest one company will be doing this as well

[jondoeuk]

Phase I, Dose-escalating, Clinical and Pharmacokinetic Study of Humanized Сhimeric Anti-CD47 Antibody in Patients With Verified Diagnosis of Breast Cancer ( ASSIST-II ) https://clinicaltria...erm=cd47&rank=2

 

Clinical and Pharmacokinetic Study of Humanized Anti-CD47 Antibody as Single Agent in Patients With Solid Tumors (ASSIST) https://clinicaltria...erm=cd47&rank=1

[jondoeuk]

Inhibrx's first immuno-oncology therapeutic is a highly differentiated antibody targeting CD47 that entered clinical studies in early 2015. INBRX-103 targets CD47 on cancer cells. CD47 binds to SIRPα on macrophages and sends a ''don't eat me'' signal thus protecting cancer cells from being engulfed and eliminated (phagocytosis). Cancer cells utilize CD47 to counter their own surface pro-phagocytic molecules and avoid phagocytosis. INBRX-103 blocks the CD47-SIRPα interaction thereby facilitating efficient phagocytosis and elimination of cancer cells. Inhibrx's CD47 antibody could be broadly applicable across all tumor types and has a pre-clinical efficacy and safety profile distinct from other CD47 targeting therapeutics with superior efficacy https://clinicaltria...how/NCT02367196

[Logic]

I can't help thinking that Cg-MAF may be a very good adjunct to anti CD47:

http://www.longecity...r-magic-bullet/

 

The CD47 antibodies would eliminate the''don't eat me'' signal sent from cancer cells to macrophages, while Cg-MAF would kick said macrophages into high gear.

 

NB the similar effect from Mistletoe posted by vitaminboss:

http://www.longecity...ndpost&p=282090

[Logic]

Inhibrx's first immuno-oncology therapeutic is a highly differentiated antibody targeting CD47 that entered clinical studies in early 2015. INBRX-103 targets CD47 on cancer cells. CD47 binds to SIRPα on macrophages and sends a ''don't eat me'' signal thus protecting cancer cells from being engulfed and eliminated (phagocytosis). Cancer cells utilize CD47 to counter their own surface pro-phagocytic molecules and avoid phagocytosis. INBRX-103 blocks the CD47-SIRPα interaction thereby facilitating efficient phagocytosis and elimination of cancer cells. Inhibrx's CD47 antibody could be broadly applicable across all tumor types and has a pre-clinical efficacy and safety profile distinct from other CD47 targeting therapeutics with superior efficacy https://clinicaltria...how/NCT02367196

 
...CD47 antibody (CC-90002) does not induce RBC agglutination [clumping]...therapeutic strategies aimed at targeting CD47 have the potential to be deployed in a broad range of oncology indications as a backbone of cancer treatment...

https://oncologydisc...ncology-target/

The Patent:
http://www.freepaten...20130224188.pdf

[jondoeuk]

 

Inhibrx's first immuno-oncology therapeutic is a highly differentiated antibody targeting CD47 that entered clinical studies in early 2015. INBRX-103 targets CD47 on cancer cells. CD47 binds to SIRPα on macrophages and sends a ''don't eat me'' signal thus protecting cancer cells from being engulfed and eliminated (phagocytosis). Cancer cells utilize CD47 to counter their own surface pro-phagocytic molecules and avoid phagocytosis. INBRX-103 blocks the CD47-SIRPα interaction thereby facilitating efficient phagocytosis and elimination of cancer cells. Inhibrx's CD47 antibody could be broadly applicable across all tumor types and has a pre-clinical efficacy and safety profile distinct from other CD47 targeting therapeutics with superior efficacy https://clinicaltria...how/NCT02367196

 
...CD47 antibody (CC-90002) does not induce RBC agglutination [clumping]...therapeutic strategies aimed at targeting CD47 have the potential to be deployed in a broad range of oncology indications as a backbone of cancer treatment...

https://oncologydisc...ncology-target/

The Patent:
http://www.freepaten...20130224188.pdf

 

 

I've just come across some early data on Stanford University's antibody (Hu5F9-G4) http://abstracts.asc...176_162472.html

 

The 1 mg/kg dose resulted in a mean RBC CD47 receptor occupancy of 91% ± 3% [95% CI 86 – 93%], indicating target saturation with no G3 anemia, and was selected as the Priming Dose. Sixteen patients have been enrolled, two patients (adenoid cystic ca) receiving weekly doses in Part A (0.1 mg/kg and 1 mg/kg) had stable disease for 16 and 8 months on continuous weekly drug dosing, respectively. Not great if you ask me. But still early days

Edited by jondoeuk, 24 May 2016 - 06:33 PM.

[mag1]

A non-solid tumor indication might have a better chance of success.

 

 

http://trilliumthera...47/default.aspx

 

http://trilliumthera...ng/default.aspx

 

https://clinicaltria...=TTI-621&rank=1

[jondoeuk]

A non-solid tumor indication might have a better chance of success.

 

 

http://trilliumthera...47/default.aspx

 

http://trilliumthera...ng/default.aspx

 

https://clinicaltria...=TTI-621&rank=1

 

Their construct was done to err on the side of caution and because at the time they didn't have enough money to produce another. However they do now http://www.fiercebio...out-forty-seven and are already work on it. The original uses an IgG4 which comes at the expense of efficacy. Trillium on the other hand use a IgG1 Fc which not only should be more effective but could also stimulate an effector function too. However you may need other agents  http://www.ncbi.nlm....pubmed/27091975

Edited by jondoeuk, 24 May 2016 - 10:48 PM.

[mag1]

This is very exciting!

We are getting close.

1 + 1 = 10

 

Trillium has another one on the go CD200

http://trilliumthera...ab/default.aspx

 

Adding CD47 with PD1 and/or CTLA-4 begins to get interesting.

All the pharmas must now have a pretty good idea what others are out there.

 

There will be amazing to watch unfold!

[jondoeuk]

Toronto, Ontario, August 17, 2016 – Trillium Therapeutics Inc. (NASDAQ: TRIL; TSX: TR), a clinical stage immuno-oncology company developing innovative therapies for the treatment of cancer, announced today that the US Food and Drug Administration (FDA) has provided the company clearance to initiate a Phase 1 clinical trial of its lead drug candidate, TTI- 621 (SIRPaFc), in solid tumors and mycosis fungoides. Patient enrollment is anticipated to commence by the end of the year. Trillium is developing TTI-621 as a novel checkpoint inhibitor of the innate immune system, and the drug is currently being evaluated in an ongoing Phase 1 dose escalation study in patients with relapsed or refractory hematologic malignancies.

 

“The FDA’s acceptance of this IND application is another important milestone for our company, as the study of TTI-621 in select tumor types could lead to a more thorough understanding of its mechanism of action, and may bring us one step closer to a much needed treatment option for patients,” said Dr. Niclas Stiernholm, chief executive officer of Trillium Therapeutics. “We seek to gain insight into the tumor micro-environment before, during and after treatment with TTI- 621. This will help us learn how to best use TTI-621 CD47 blockade in combination with other anti-cancer drugs and better design the commercial development path for this agent.”

In the multicenter, open-label, Phase 1 trial, TTI-621 will be delivered by intratumoral injection in patients with relapsed and refractory, percutaneously-accessible cancers. Patients will be enrolled in sequential dose cohorts to receive intratumoral injections of TTI-621 that increase in dose and dosing frequency to characterize safety, pharmacokinetics, pharmacodynamics and preliminary evidence of antitumor activity. In addition, detailed evaluation of serial, on-treatment tumor biopsies of both injected and non-injected cancer lesions will help characterize tumor microenvironment changes anticipated with CD47 blockade.

 

http://trilliumthera...es/default.aspx

[jondoeuk]

This is very exciting!

We are getting close.

1 + 1 = 10

 

Trillium has another one on the go CD200

http://trilliumthera...ab/default.aspx

 

Adding CD47 with PD1 and/or CTLA-4 begins to get interesting.

All the pharmas must now have a pretty good idea what others are out there.

 

There will be amazing to watch unfold!

 

I will add some links to this post in another reply as I'm having trouble doing this

Edited by jondoeuk, 19 August 2016 - 11:37 PM.

[jondoeuk]

Intratumoral injections of a number of drugs seems promising. I hope a few combo trials will start with TTI- 621  http://www.ncbi.nlm....pubmed/23603859 http://www.bloodjour...13/15/3546.long http://www.jci.org/articles/view/64859 https://ash.confex.c...Paper80842.html https://ash.confex.c...Paper83393.html http://www.ncbi.nlm....pubmed/25959818 http://www.ncbi.nlm....pubmed/25529558 http://www.ncbi.nlm....les/PMC4201984/ http://www.ncbi.nlm....les/PMC4075973/ http://cancerablatio...5/11/poster.pdf http://www.immunedes...-IL12_FINAL.pdf http://files.shareho...cal_-_FINAL.pdf http://files.shareho...e_2015FINAL.pdf http://files.shareho...101_-_FINAL.pdf http://www.ideraphar...oster_Final.pdf

 

 

 

There is data for this approach in humans http://www.immunedes...May2016-v01.pdf http://cancerablatio...5/11/poster.pdf http://files.shareho...cal_-_FINAL.pdf http://www.ziopharm....o_gbm_final.pdf

[jondoeuk]

[jondoeuk]

[mag1]

Anyone have any idea on whether guadecitabine would help in metastatic cisplatin refractory testicular cancer with mets to the brain? Would it cross the BBB?

Guadecitabine is a dinucleotide like the STINGs. Do STINGs cross the BBB?

It looks like a strong choice especially in non-seminoma testicular cancer.

Edited by mag1, 22 March 2017 - 09:48 PM.

[jondoeuk]

Updates from $TRIL http://trilliumthera...te/default.aspx

 

AACR presentations:
Today the company presents two preclinical posters at the 110th American Association for Cancer Research Annual Meeting in Washington, DC: 

The first presentation (Abstract #2646), entitled “Intratumoral Delivery of TTI-621 (SIRPaFc), a CD47-Blocking Immunotherapeutic, Inhibits Tumor Growth and Prolongs Animal Survival in a Subcutaneous B Cell Lymphoma Model,” demonstrated that TTI-621 was efficacious when injected directly into tumors in a xenograft model. In addition, intratumoral TTI-621 increased the phagocytosis of tumor cells by both M1 and M2 tumor-associated macrophages. These data support the clinical evaluation of direct tumor injections of TTI-621. A Phase 1 study of intratumorally delivered TTI-621 in patients with percutaneously accessible solid tumors and mycosis fungoides is ongoing (NCT02890368). 

The second presentation (Abstract #2653), entitled “The Anti-Myeloma Activity of TTI-621 (SIRPαFc), a CD47-Blocking Immunotherapeutic, is Enhanced When Combined With a Proteasome Inhibitor,” showed that TTI-621 exhibits anti-myeloma activity on its own that is further enhanced by combination with FDA-approved proteasome inhibitors, such as bortezomib and carfilzomib. These data provide a rationale to evaluate a combination cohort of TTI-621 and a proteasome inhibitor in multiple myeloma patients. 

Clinical update:
The company is currently enrolling patients in the expansion phase of its ongoing Phase 1 trial of TTI-621, in patients with multiple hematologic malignancies (NCT02663518). Trillium is providing this clinical update in conjunction with the AACR presentations.

To date, 33 evaluable patients have been enrolled into the expansion phase of the trial, with several patients demonstrating preliminary evidence of anti-tumor activity. In the AML cohort, one patient with minimal residual disease (consisting of 0.7% abnormal blasts at baseline) obtained a complete molecular remission after 4 infusions of TTI-621. A second marrow analysis at week 8 confirmed a complete molecular remission, the patient continues to tolerate weekly infusions of TTI-621 and remains in continued remission for 15+ weeks.

In the TTI-621/rituximab combination cohort, 3 of 6 patients who have had at least one interval PET/CT restaging obtained partial metabolic responses, as demonstrated by decreased tumor activity on PET/CT scans. These patients with CD20-positive, B-cell lymphoma received weekly IV infusions of TTI-621 and rituximab. Manageable infusion reactions occurred in most patients after the first infusion of TTI-621 and the combination therapy has been associated with acceptable outpatient tolerability. These responding patients remain on treatment and progression-free for 19+ (DLBCL), 18+ (transformed lymphoma), and 8+ weeks (follicular lymphoma) in continuing follow-up. 

“Patients with treatment-refractory lymphoma and acute myeloid leukemia continue to represent a pronounced unmet clinical need,” said Trillium’s Chief Medical Officer, Eric Sievers, MD. “We and the clinical investigators are encouraged that several of the patients treated with the TTI-621/rituximab combination obtained robust lymphoma regressions. Moreover, while anecdotal, the achievement of complete molecular remission in a patient with relapsed AML is intriguing. Taken together, we believe that the multiple clinical responses observed across varied hematologic malignancies to date is promising.”

Details of these clinical responses with further follow-up will be reported at scientific symposia later this year. 

[jondoeuk]

Anyone have any idea on whether guadecitabine would help in metastatic cisplatin refractory testicular cancer with mets to the brain? Would it cross the BBB?

Guadecitabine is a dinucleotide like the STINGs. Do STINGs cross the BBB?

It looks like a strong choice especially in non-seminoma testicular cancer.

 

I can't find any evidence it crosses the BBB. Is salvage therapy an option?

[mag1]

possible Leptomeningeal metastasis after initial response from treatment for testicular cancer

 

Would there be any treatment available for such an illness?

Testicular cancer has been so successfully treated with chemotherapy, though I am unclear whether

any traditional medical treatment would be available for this form of progression.

Edited by mag1, 05 April 2017 - 12:56 AM.

[mag1]

Using ex vivo SIRPA inhibited macrophages with antibodies as a cancer therapy.

 

Possible toxicity from SIRPA CD47 therapy?

 

"such molecular treatments reproducibly cause rapid loss of many circulating blood cells, as macrophages now attack some healthy cells as well. In addition to causing anemia, some mice with depleted CD47 die from auto-immune disease."

 

https://www.scienced...70719173705.htm

http://www.cell.com/...9822(17)30706-6

 

This approach appears to be technically easy: extract macrophages, treat with SIRPA-CD47  and other antibodies, infuse.

As is noted above Trillium is working on a SIRPA product, thus the needed elements are approaching clinical use.

 

Wonder whether Trillium would consider going ex vivo?

Any safety concerns might be reduced while amplifying the benefits.

Edited by mag1, 20 July 2017 - 04:46 PM.

[jondoeuk]

Using ex vivo SIRPA inhibited macrophages with antibodies as a cancer therapy.

 

Possible toxicity from SIRPA CD47 therapy?

 

"such molecular treatments reproducibly cause rapid loss of many circulating blood cells, as macrophages now attack some healthy cells as well. In addition to causing anemia, some mice with depleted CD47 die from auto-immune disease."

 

https://www.scienced...70719173705.htm

http://www.cell.com/...9822(17)30706-6

 

This approach appears to be technically easy: extract macrophages, treat with SIRPA-CD47  and other antibodies, infuse.

As is noted above Trillium is working on a SIRPA product, thus the needed elements are approaching clinical use.

 

Wonder whether Trillium would consider going ex vivo?

Any safety concerns might be reduced while amplifying the benefits.

 

CARMA Therapeutics https://carmatherapeutics.com are working on CAR engineered macrophages. In this they state: '' Lastly, we demonstrated that the blockade of the anti-phagocytic CD47/SIRPα axis enhanced the phagocytic capacity of CARMA.'' http://cancerres.aac...Supplement/4575 So they'd be more likely to take this forward when compared to Trillium.

 

$TRIL will present the following at SITC: The anti-tumor effect of radiation therapy is enhanced with the addition of TTI-621 (SIRPaFc), an immune checkpoint inhibitor blocking the CD47 “do not eat” signal https://www.sitcance...ination-therapy 

 

The checkpoint inhibitor TTI-621 (SIRPaFc) stimulates innate and adaptive immune responses in patients with hematologic and solid tumor malignancies https://www.sitcance...mune-monitoring

Edited by jondoeuk, 23 September 2017 - 12:22 PM.

[jondoeuk]

I came across the following (the link appears broken): ''Dr. Akilov reported about a rapid response see with TTI-621 in a 67-year Sézary syndrome patient, who had multiple prior therapies and relapsed. After a single intratumoral injection (3 mg), the lesion showed regression on Day 3 and further reduction on Day 7. There was also a rapid reduction of SS tumour lymphocytes in peripheral blood from 56.2% at baseline to 26.9% on Day 3 and 5.8% on Day 5. The reduction of SS cells was accompanied by a transient increase in macrophages from 3.9% at baseline to 6.1% on Day 3. A significant increase in the percentage of NK cells and naïve CD8+ cells on Day 3, followed by a significant increase of CD4+ and CD8+ effector memory T cells on Day 5, was also observed after the injection. While the cutaneous tumour lesion regression was durable, most of the rapid immune cell changes in peripheral blood appeared transient, as SS cells, macrophage, CD8+ naïve T cell, and effector memory T cell levels all returned to baseline levels on Day 7. However, a single subcutaneous injection of PEGylated Interferon-α2a (90 ug) led to rapid reduction again of SS cells to 0.6% 7 days later and caused the complete regression of the cutaneous tumour lesion on Day 21. Such rapid response is usually not seen with PEG-IFNα2a alone.

 

The data, although in only 1 patient, suggest that the drug may have a rapid impact on both the local tumour lesion and the innate and adaptive immune response, suggesting that monotherapy is likely quite active in SS/CTCL. Although most of the systematic immune cell changes were transient, it may be due to the transient systematic PK profile of a single local injection of the drug with a half-life of around 4 days, which however could be improved with repeated injections. Moreover, the impact on both innate and adaptive immune cells seen after it was administered indicates promising combination opportunities with other immunotherapies in CTCL, as evidenced by the likely synergistic effects seen with PEG-IFNα2a in this SS patient.''

 

Here is the PR from Trillium http://trilliumthera...ce/default.aspx

 

[jondoeuk]

4076 A Single Direct Intratumoral Injection of TTI-621 (SIRPαFc) Induces Antitumor Activity in Patients with Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Preliminary Findings Employing an Immune Checkpoint Inhibitor Blocking the CD47 “Do Not Eat” Signal

 

Methods

A Phase 1, multicenter, open-label study is ongoing to characterize the safety and tolerability of intratumoral injection of TTI-621 (NCT02890368). Eligible patients (pts) are adults with relapsed or refractory mycosis fungoides/Sézary syndrome or percutaneously-accessible solid tumors who have progressed on standard anticancer therapy or for whom no other approved therapy exists. Pts are enrolled in sequential cohorts to receive a single intratumoral injection of TTI-621 at increasing dose levels to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity. Repeat TTI-621 intratumoral dosing has recently been initiated. Serial, post-injection biopsies are collected to assess the temporal impact of TTI-621 on the tumor microenvironment.

Results

Nine pts (6 M/3F, age 57–85 years) have been enrolled as of July 2017. Diagnoses include mycosis fungoides/Sézary syndrome (N=6), melanoma (N=1), leiomyosarcoma (N=1), and squamous cell carcinoma (N=1). A single intratumoral injection of 1 mg, 3 mg, or 10 mg TTI-621 has been well tolerated by all enrolled pts. The most frequently reported adverse events were fatigue in 5 pts, chills in 4 pts, and decreased appetite in 3 pts. All treatment-related AEs were Grade 1 or 2 in severity. No dose limiting toxicity has been observed to date. All 6 pts with mycosis fungoides/Sézary syndrome experienced decreases in tumor size and/or decreased circulating Sézary cells (3 of 3 pts) as determined by a decrease in a peripheral clonal T-cell population or CD4:CD8 ratio after a single intratumoral injection of TTI-621. Responses ranged from loco-regional to systemic effects. One pt with localized refractory mycosis fungoides on the dorsum of the foot obtained a complete response of the injected lesion that is ongoing after 17+ weeks of follow up. NanoString analysis of peripheral blood and tumor tissue pre- and post-intratumoral injection of TTI-621 indicated alterations in genes associated with activation of the innate immune system and upregulation of IFN-associated genes.

Conclusions

These preliminary Phase 1 data suggest that mycosis fungoides and its leukemic variant, Sézary syndrome, are highly responsive to a single dose of TTI-621 delivered by intratumoral injection. One pt achieved a complete response of the injected lesion and 5 additional pts experienced decreases in tumor size and/or decreased circulating Sézary cells. Intratumoral injections were well tolerated by all pts. Evidence of innate immune activation was documented, consistent with the proposed function of TTI-621 as an innate immune checkpoint inhibitor.

 

https://ash.confex.c...aper100952.html

4116 TTI-621 (SIRPαFc), an Immune Checkpoint Inhibitor Blocking the CD47 "Do Not Eat" Signal, Induces Objective Responses in Patients with Advanced, Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

 

Methods

A phase 1, open-label, multicenter study is ongoing to evaluate the activity of weekly IV infusions of TTI-621 in multiple cohorts of adult patients (pts) with relapsed or refractory malignancies. Eligible pts are those who have progressed on standard anticancer therapy (including rituximab for pts with B-cell lymphomas), or those for whom no other approved therapy exists (NCT02663518). This data disclosure comprises all consecutively enrolled pts with diffuse large B-cell lymphoma (DLBCL) who received, at a minimum, 0.2 mg/kg/week TTI-621 monotherapy or 0.1 mg/kg TTI-621 in combination with 375 mg/m2/week rituximab for 8 weeks, after which TTI-621 monotherapy was permitted.

Results

As of June 1, 2017, 14 evaluable pts with DLBCL (7M/7F, age 42–72 years) have been enrolled and treated: 6 pts received TTI-621 monotherapy and 8 pts received TTI-621 plus rituximab. The number of prior systemic therapies ranged from 2 to 13; 6 pts had received prior autograft. Weekly outpatient treatments have been well tolerated. Mild-to-moderate infusion-related reactions were experienced by 9 pts following the first dose of TTI-621. Transient, dose-dependent decreases in platelets and leukocytes were generally without clinical sequelae. Objective responses were observed for 5/14 pts (36%): 1/6 pts treated with TTI-621 monotherapy and 4/8 pts treated with TTI-621 plus rituximab. Two pts attained complete responses (CR). One CR occurred in a pt treated with TTI-621 monotherapy who remains in continued CR at 20+ weeks. The second CR was in a pt treated with TTI-621 plus rituximab who remains in continued CR at 12+ weeks.

Conclusions

Weekly IV dosing employing TTI-621 to block the CD47 “do not eat” signal as monotherapy or in combination with rituximab was well tolerated. Treatment was associated with preliminary and promising anti-tumor activity in pts with advanced DLBCL as evidenced by 2 CRs and 3 PRs among 14 pts.

 

https://ash.confex.c...aper100943.html

[jondoeuk]

Here are the two posters $TRIL presented at SITC

 

The Anti-tumor Effect of Radiation Therapy is Enhanced with the Addition of TTI-621 (SIRPαFc), an Immune Checkpoint Inhibitor Blocking the CD47 “Do Not Eat” Signal http://s2.q4cdn.com/...Poster-P272.pdf

 

The Checkpoint Inhibitor TTI-621 (SIRPaFc) Stimulates Innate and Adaptive Immune Responses in Patients with Hematologic and Solid Tumor Malignancies http://s2.q4cdn.com/...poster5-P42.pdf

Edited by jondoeuk, 14 November 2017 - 04:41 AM.