Podcasts about Aadi

This podcast covers episodes 11,623 to 11,628. Bernie is keen that Aadi maintains his lie about the robbery at the Corner Shop. Noah's back and wastes no time trying to encourage Theo to a conversion therapy session. Carla feels helpless as she tries to support Swain through her therapy. Lou has one last throw of the dice as she tries to avoid a lengthy jail term for twatting Gary. Tensions are high between Sam and Lily following the lockdown incident at the school. Carl's loan sharks are circling while he looks to Debbie for salvation. Audrey loves the drama. David mistrusts air fryers. Ryan read a book.

We're not going to be able to record at all this weekend, so Episode #690 of the podcast is coming out early, focusing on what went on in Weatherfield on the 21st and the 23rd July (Episodes #11,623 - 11,626). It was a tough week for Theo this week when Noah reared his head again with a Bible in one hand and a leaflet to his latest conversion session in the other. Can Theo let go of his past and stay true to himself? Also this week, Ryan's left reeling when Debbie gives him an unexpected kiss - a friendly gesture from a grateful boss, a side effect of her dementia.. or something much murkier? Meanwhile, Aadi scrambles to keep Dev from uncovering the truth about the staged robbery, Lou braces herself for a likely prison sentence, and Sam mysteriously vanishes during Audrey's birthday party. Could Lily's antics last week be to blame? Not much in the way of Corrie news this week so we give The Kabin a swerve, and finish off with a couple of pieces of listener feedback. Street Talk - 00:11:24 Feedback - 01:50:39

On our latest podcast, we chat about the episodes of Coronation Street shown between the 14th and the 18th July (Episodes #11,617 - 11,622) Another big event episode this week – and yes, another prison break and another hostage situation. This time, it was Mick's turn in the spotlight, but how did it measure up to recent rampages? And did Corrie really need to return to that same well so soon after Rob Donovan's escape? Meanwhile, Lily's got a new head and, with it, a brand new attitude – but was her callousness towards Sam during the school break-in in any way justified? Also this week, Aadi and Brody stage a robbery, there's a gazump-off between Lisa and Carla, and while Gary's head might be healing, his pride has taken a serious hit... Up next, we take a quick trip to The Kabin, where we chat about the competition launches by This Morning to get a Corrie fan's pooch a walk-on part in the show, and we round off the week with more of your feedback.  Street Talk - 00:14:39 The Kabin - 02:37:51 Feedback - 02:44:54

This podcast covers episodes 11,617 to 11,622. In retrospect, it turns out that it was a really bad idea to let a man on remand for killing a police officer work in the prison laundry. Brody is devastated when both paternal figures in his life reject him on the same afternoon. Nick is furious when he discovers that Lily kept Sam locked out of a safe room during the incident at the school. Debbie causes concerns when she puts in an offer £30,000 over the asking price for Number 6. Gary discharges himself from hospital and at home he reacts badly to a bit of banter from Liam. Aadi cooks up a hare-brained scheme to regain the money he lost that time he over-ordered whisky. Hope's worried for Chesney. Lauren's got new lippy. Sarah huffs Kit's oxters.

Col Ajay Raina, Aadi Achint, Sanjay Dixit on Pakistan, China, America | Deep Insights on World Order

Aadi poi Aavani vandha daappula varuvaan - INDIAN

On our latest podcast, we discuss the episodes of Coronation Street shown on the 10th and the 11th July (Episodes #11,613 - 11,616). This week's episodes finally saw the reveal of what happened to Gary the night of the party to put him into the coma - and to the surprise of no-one, it's Lou who's right at the heart of it. Will she be able to talk her way out of this one? Meanwhile, Lisa starts her therapy sessions and finds herself opening up a lot more than she was expecting about Becky. Also this week, Lauren and Aadi get closer, an insecure Kevin continues to lie about his health, and Dee-Dee gets Laila christened in secret. Next up on the podcast, it's The Kabin, and we chat about the nominations for this year's Inside Soap Awards. We finish things off with more of your fantastic feedback. Street Talk - 00:11:26 The Kabin - 01:51:36 Feedback - 02:13:56

This podcast covers episodes 11,609 to 11,616. Todd confronts Millie about his suspicions of her pregnancy. Kev is worried about the gulf growing between him and Abi and contrives a foolhardy plan to keep her. Dee Dee has trouble respecting the boundaries of the adoption agreement with James. Steve panics when he lets slip that he's falling for Cassie. Aadi feels responsible for Racist Kelly when she is finally released from hospital. Conflicted by Tinker and Becky's deaths, Swain struggles to open up during her first therapy session. Maria's concerns for Gary grow while Nina continues to worry about her own involvement. Fiz can't change a flat. Jack takes a penalty. Carla puts cheese in her bath.

India is Preparing For Something Big? | Importance of Skardu for India | Col Ajay Rina, Aadi Achint, Sanjay Dixit

Nur Khan Base Secrets | Decoding Dy COAS Press Conference | Geopolitics ft. Aadi Achint

We're now six months into 2025, which can only mean one thing – it's time for our Coronation Street mid-year review! It's been a dramatic start to the year, with a string of big exits – from Mason's tragic death to Daisy's glamorous escape to Bali – but is Corrie shedding too many characters at once? We dive into the growing trend of event episodes, including the Platt house fire, Mick and Kit's powerful flashback, Aadi's ill-fated party and more. Plus, we discuss the arrival of the Michaelis family, the surprise return of Rob Donovan, and what the increased reliance on those hospital and police sets might mean for the show's future. No stone is left unturned in our deep dive into Corrie's 2025 so far!

This podcast covers episodes 11,603 to 11,608. Brody and his new best friend Dylan crash the party at Number 7 and take along a little something-something to get things moving. Racist Kelly worries she's universally hated then has her drink accidentally spiked at the party. Steve and Cassie are an item and Tracy congratulates them by making some ridiculous divorce demands. Debbie doesn't take too kindly to Kev and Ronnie sticking their noses into how she will be cared for in the future. Todd is shocked when he discovers Millie drinking lager in the community garden. Nina tries to remember details of the troubling events after the party, while Maria wonders where on earth Gary's disappeared to. Kit's so done with this week. Aadi's a disappointing snog. Summer is a hoot.

Conor and Tara share how Wednesday changed the world for their son and AADI's David McCarthy says dogs bring kids from overload to safety Hosted on Acast. See acast.com/privacy for more information.

Middle East Map is Going to Change? | China - Pak - India | Sheikhs Happy, Mullahs Sad | Aadi Achint

On our latest edition of the podcast, we chat about the episodes of Corrie shown between the 16th and the 20th June (Episodes #11,597 - 11,602) This week saw Glenda putting on a drag night at the Rovers - but the real drag was most definitely Theo, who Todd seems to be besotted with despite him having more red flags than the Swiss embassy. Meanwhile, the truth about Debbie's condition comes out on Friday and she does a runner - does the fact that she doesn't turns up on the Victoria Gardens bench by the end of the episode mean we're in for a longer term missing person story? Also this week, Lou locks lips with Gary, Aadi plans a Summer party and Dee-Dee and James clash over her plans for a religious upbringing for Laila. Up next on the podcast is The Kabin, where we share our thoughts on the reports that Jack Carroll has quietly left the show, and we finish things off with a bumper feedback session. Street Talk - 00:23:49 The Kabin - 02:41:03 Feedback - 02:53:01

This podcast covers episodes 11,597 to 11,602. An under pressure Swain is too quick to arrest Brody and isn't prepared for the consequences. Sally makes a bold decision to report Lou to the social services. James is absent from Laila's vaccinations and becomes concerned that Dee Dee is regretting giving her up. Todd is depressed at the state of his relationship and is further knocked down when he sees Theo is back on the gay apps. Maria is released after a night in the cells and is shocked when Gary is still defending Lou. Aadi takes it to heart when Bernie suggests he's getting old before his time. Debbie finds it increasingly difficult to keep the truth of her dementia from her family. Daniel steals a poppadum. Billy just won't shut up. Rafael's been on his own all day, dammit.

Pakistan - America Playing Games with India | Modi has Other Big Plans | Aadi Achint, Sanjay Dixit

China - Pakistan - Trump Axis | Is Trump Against Modi? | Aadi Achint, Sanjay Dixit

India Had Hit Pakistan Nukes | 8 New Big Targets Revealed | Drone Warfare ft. Aadi Achint

Big Game Decoded - China - Pak - Trump - Bangladesh | No Indian Jets Shot Down ft. Aadi Achint

Modi Roars on Pakistan from Bhuj | Pak Rattled | More Operation Details Now Out | Aadi Achint

How India has Hit the Reset Button | Pakistan Shattered | Indian Army Pinpoint Hitting | Aadi Achint

Modi's Swag Against Pakistan | Nuclear Story | Adampur Air Force Base | Aadi Achint, Ramnik Mann

Indian Forces have Finished Pakistan | DGMO ने तो धो डाला | Aadi Achint & Sanjay Dixit

Indian Forces Hammer Pak | Multiple Strikes on Airbases, Drone Launchers | Aadi Achint, Col Raina

Indian Air Force Still in Action | Pakistan's NUKES Finished? | Col Ajay Raina, Aadi Achint

Indian Forces have Finished Pakistan | DGMO ने तो धो डाला | Aadi Achint & Sanjay Dixit

This podcast covers episodes 11,561 to 11,566. Dee Dee begins to bond with Laila just as James returns from America. After Danielle reports Theo missing, he returns drunk to the street and tells Todd about his experiences as a child in a religious family. Jenny finds herself at a low ebb following Daisy's betrayal while Rita encourages her to start anew. After an unseen assault in a pub parking lot, it appears that Mick and DC Green have a secret past together, probably not like that. Racist Kelly is spooked when she continues to get threatening messages and begins to have suspicions about the identify of her blackmailer. Carl tries to position himself as an assistant to Debbie and is disappointed when she goes in a different direction. While George attempts spontaneity, Julie and Eileen's day out in the country takes a devastating turn. Aadi's plums are sweet and firm. Jake needs to wait for that Xbox. Here comes the rain again.

ATTACK COMING SOON - JAMMERS DEPLOYED | Internal Enemies | What is Modi Planning | Aadi Achint

India Attacks Lahore, Karachi via Drones | Pak Midnight Missile Attack | Col Ajay Raina, Aadi Achint

Operation Sindoor - India Ready to Attack Pakistan | Jammu, Chandigarh | Col Ajay Raina, Aadi Achint

India Prepares to HIT BACK at Pakistan | Baloch Independence | Aadi Achint, Col Ajay Raina

(0:00) Intro(1:06) Ehsan Faramoshi — Sabse Bura Aib(2:14) Mufti Sahab ke Purane Dost ka Zikr(3:07) Ehsan Faramosh logon par gussa kyun aata hai?(4:09) Allah ke Behsab Ehsanaat(4:50) Aasaan Ehsaanmandi kya hoti hai?(5:48) Mushkil Ehsaanmandi — Asliyat kya hai?(6:29) Kafir ki Ehsan Faramoshi — (Allah aur waldain ke huqooq na maanna)(6:29) MTM's Advice for West-Influenced Youth(11:04) Muslim vs Kafir in Shukar Guzari — Kaun behtar?(12:40) Allah ka Matloob Shukar — Kya Allah bhi Shukar chahta hai?(13:12) Friends vs Relatives — Ravayya aur haqeeqat(14:57) Business ka Asool — Fraud se kaise bacha jaye?(17:34) Khawateen ka paisa khane wale Bhai aur Shohar(18:25) Paison ke mamlaat mein Aik Number banne ka tareeqa(19:26) Women Rights ke Mubham Naare(20:48) Kafir Allah ke huqooq ko kyun nahi maanta?(21:42) Ehsaan ke lehaz se Shukar karna(22:32) In 4 ke huqooq sabse zyada pamaal kiye jaate hain(23:54) Is 1 ka haq sabse zyada ada kiya jaata hai(24:40) Allah ke Ehsanaat — Kitne hain asal mein?(25:08) Insani Aankhon ki Qeemat — Andazah kab hota hai?(28:08) Kafir ki Na-Shukri ki misaal(31:29) Allah ki Qudrat ke Kamalaat — 5 Sensors aur Honth ka Nizaam(34:27) Amazing Male-Female Pairing System — Fitrat ka tajziya(37:17) Qur'an vs Scientific Theories — Titli, Phool, Deemak, Cheentiyan, Machhar(41:12) Aik Doctor ki “So-Called” Research on Brain(42:17) Islam vs Nazriya-e-Irtiqa(44:04) So-Called Evolution Theories ka postmortem(46:01) Kaainaat ka wajood kaise aaya?(47:28) Aulad: Chehre ki roshan rozaan(48:37) Child Schema — Bachon ke chehre par attract karne wali lines(49:52) Sabse Bari Na-Shukri — Har ni'mat ko sirf nature kehna(51:35) Guthli se aam banna — Allah ki qudrat ka nizaam(53:31) Doodh aur Ghee — Qeemti ni'matain jo bhool jaate hain(54:17) Scientists about Evolution — Kya wo confuse hain?(55:13) Musalman ki Shukar Guzari(55:46) Kafir ki Na-Shukri(57:22) Ilm vs Aqal — Kya farq hai?(1:00:46) Atheist University Professor ka Taleemi Andaz(1:02:40) Creation without Creator? — Aqlmandi ya ghaflat?(1:04:35) Mufti Sahab ka Sawal Aik Atheist se(1:06:08) Allah ke Wajood ke Daleel — Naak, kaan ka mechanism(1:08:35) Mufti Taqi Usmani ka Waqia — Africa mein phoolon ki analysis(1:09:24) Nanhiyal, Dadhiyal, Susral — Risthon se milti izzat(1:11:31) Ghar Damad banne ka masla(1:12:13) Allah ke Ehsanaat(1:12:56) Bani Israel ki Na-Shukri(1:13:47) Chaman/Quetta mein Mufti Sahab ka tajurba — Bina namak ke khana(1:14:50) Allah ki ni'maton ka shukar ada karne ka tareeqa(1:15:46) Mufti Rasheed Ahmed DB ka Isteghna(1:16:33) Museebat mein Shukar Guzari — Kaise mumkin hai?(1:17:12) Waqia: 8 Saal ki beti ki maut (Eid ke doosre din) — Sabir Baap(1:19:29) Waqia: Bachay ki Maut par Na-Shukra Baap(1:20:34) Allah ka Haq ada karne wale kaam(1:21:38) Kanjoosi ka Aadi(1:23:36) Janwaron par Zulm(1:24:44) Mard ke liye Darhi rakhna(1:26:28) Aurat ke liye Parda karna(1:27:01) Dating(1:27:46) Khulasa Bayan + Dua Hosted on Acast. See acast.com/privacy for more information.

Pakistan is scrambling. Indian Rafales breach POK. Jammers deployed. PM Modi's military escalation seems locked in. Are we heading for the final strike? Aadi Achint breaks it down.

More Big Actions Coming From Modi - Military Options | Pakistan की फटी | LIVE QnA | Aadi Achint

Don't Take Modi Lightly - AFSPA on Border? | Pakistan Anti India Rant | Amit Shah | Aadi Achint

Who's Behind the Waqf Uprising in Bengal | Chicken Neck | Dangerous Game Exposed! | Aadi Achint

Change in Modi s Political Strategy, Collegium NJAC, WAQF I Aadi Achint Interviews Sanjay Dixit

A New Map of Pakistan | US Envoy in Afghanistan | Bangladesh Headed to Civil War | Aadi Achint

Pakistan is in deep turmoil as Baloch, Sindhi, and Pashtun groups unite against the state, intensifying the resistance in Balochistan. In a desperate move, Pakistan is once again blaming India for the uprising, but is this just an excuse to cover its own failures? With multiple insurgencies brewing, is Pakistan heading toward a breakup? Sanjay Dixit, Ajay K Raina, and Aadi Achint analyze Pakistan's deteriorating control over Balochistan, the growing anti-Pakistan sentiment among ethnic groups, and the geopolitical consequences of a fractured Pakistan.

Dr. Shannon Westin and her guest, Dr. Breelyn Wilky, discuss the JCO article, "“Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas." TRANSCRIPT  Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on research that has been published in the Journal of Clinical Oncology. I am your host, Gynecologic Oncologist and Social Media Consultant Editor of the JCO, Shannon Westin. I serve here from the University of Texas MD Anderson Cancer Center. And I am so excited to welcome Dr. Breelyn Wilky. She's an Associate Professor and the Director of Sarcoma Medical Oncology in the Department of Medicine Division of Medical Oncology, and the Cheryl Bennett & McNeilly family endowed chair in Sarcoma Research, the Deputy Associate Director of Clinical research at the University of Colorado Cancer Center. Welcome. Dr. Breelyn Wilky: Thank you so much. I'm delighted to be here. Shannon Westin: And with all those titles, I'm super impressed that she was able to complete the manuscript that we're going to discuss today, which is “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas.” And this was published in the JCO on January 27, 2025. And please note, our participants do not have any conflicts of interest. So this is exciting. Let's first level set. Can you review with us just the current state of sarcoma incidents, survival outcomes, that kind of thing so we all know where we're starting? Dr. Breelyn Wilky: Yes. So, you know, sarcomas are really, I like to call them the black box cancer type. And the big thing is that there's really more than a hundred different kinds of sarcomas, which collectively altogether make up only 1% of adult cancers. And so we talk about these as being bone and soft tissue tumors, but really, the heterogeneity is just incredible. You're talking maybe 10,000 to 12,000 new cases of soft tissue sarcoma per year, which is pretty rare in the grand scheme of things. And the trouble with these is that while you can cure sarcomas if you find them early and they're localized, when they metastasize and spread and are not resectable, we're looking at median overall survivals of really only 12 to 18 months, even, you know, with our best therapies that we have. So, really there's just a dire need for new treatments for this really tough group of diseases. Shannon Westin: Yeah, I agree. I'm a gynecologic oncologist, and we have our little subset of sarcomas that I know there's a little bit out of every one. So I'm really excited to pull this manuscript as one of our podcasts offerings because I think we're all seeing these patients in the clinic and certainly our listeners that have sarcoma or have family members with sarcoma, this is so good to have a real focus on a rare group of tumors that have been a little bit lumped together. Now, with that being said, I know this is such a heterogeneous population, but can you briefly overview a little bit around the standard of care for treatment of recurrent sarcomas? Dr. Breelyn Wilky: We have actually been using the same drugs really since about the 1970s, and up until very recently, nothing had really challenged doxorubicin, the old ‘red devil', like we used to call it. And this has been the mainstay of treatment for metastatic sarcomas and really used across the board. In the GYN literature, for uterine leiomyosarcoma, we did see some promising activity with the combination of doxorubicin and trabectedin coming out of the French group. But, except for that study, no combination therapy or new drug has been proven better in terms of overall survival compared to doxorubicin monotherapy, really over 40, 50 years. So it's definitely a tough situation. Now, we do have other drugs that we use, so most patients will wind up getting doxorubicin-based therapy. There's a couple of other regimens that we'll reach to, like gemcitabine docetaxel. And once you get into the specific subtypes, we have some approvals in liposarcomas and leiomyosarcomas for some other drugs. But really the median progression for survival for most of these regimens is somewhere four to six months. And response rates typically are somewhere like 10%, 15% for most of these. So it's really just a very tough field and a tough group of patients to try to make an impact for. Shannon Westin: So let's talk a little bit more kind of getting focused on what you've studied here. What's been the role of immunotherapy thus far in the treatment of sarcomas maybe prior to this particular study? Dr. Breelyn Wilky: Clearly, we all know that immune therapy has just changed cancer care forever over the last few years for so many different types of cancers and diseases like melanoma and renal cell and lung cancer have just been transformed by checkpoint inhibitors specifically directed against PD-1 or CTLA-4 or both. And so, of course, you know, sarcoma docs we're super excited to try to see if these might potentially have activity in our tumors as well. I never had seen myself in my career getting into immunotherapy until I was able to run an investigator-initiated study during my role in Miami, where we combined pembrolizumab, so PD-1 inhibitor, with axitinib which was a pan-VEGF inhibitor. And lo and behold, like I had patients that I was seeing responses when other treatments, all those chemotherapies I was just talking about had failed. And one of my first patients I treated was about a 60-year-old lady with something called cutaneous angiosarcoma. So this is a blood vessel sarcoma all over her face. And we had treated her with 10 different therapies, all the chemotherapy regimens, targeted therapies, clinical trials, and nothing was working. But I put her on a phase 1 trial with a baby dose of CTLA-4 and this woman had a complete response. And so for me, once I saw it work in even just those couple of patients, like that was nothing that we'd ever seen with our chemotherapy regimens. And so that sort of shifted my career towards really focusing on this, and this is about the time where some of the studies started to come out for sarcomas. And the take home with sarcoma is about 20% of sarcomas have this sort of immune hot physiology. So what that basically means is if you look at gene expression of immune related gene signatures, or you look for infiltrating T-cells, sort of the SWAT team of our immune system, like you can find those in the tumors. And it's sort of evidence that the immune system had some clue for that 20% of patients that this was a foreign tumor and that it should be attacking it and maybe just needed a little help. But globally, about 80% of sarcomas are these immune cold tumors, which means the immune system has no clue that these things are even a threat. And there's almost no immune activation, very, very few antigens. In other cancer types, high neoantigens or tumor antigens help the immune system work better. And so that basically goes with what we've seen with trials of PD-1 or CTLA-4 blockade. About 20% of sarcomas, with some exceptions, can respond. But really 80% across the board, you're stuck, you just can't get them to be recognized. And so that's where I think this data is so interesting is there's some signals of activity in these immune cold tumors which, at least historically with the trials we've done so far, we really haven't seen that with sort of the traditional checkpoints. Shannon Westin: So I think now this is a great time to maybe talk about the study design in general, the eligibility and just give us kind of a run through of that. Dr. Breelyn Wilky: So this trial was a phase 1 trial of a drug called botensilimab, which is a next generation CTLA-4 directed immune modulator. So what makes botensilimab different is that the CTLA-4 end is very similar to other CTLA-4 inhibitors that are out there, but it's been engineered on the back end of the molecule that binds to Fc gamma receptors to basically bind tighter with higher affinity. And what this translates to in laboratory models and increasingly now in patients is it does a better job of priming, of educating our T cells, our, again, these highly intelligent antigen specific cells, but also natural killer cells. It does a better job of sort of educating those. It helps to activate macrophages and other supporting actors in the immune response. And so the idea here is that there's evidence that botensilimab may do a better job at creating new responses in immune cold tumors. The study combined either botensilimab as monotherapy or in combination with a PD-1 inhibitor called balstilimab. And this was all comers, really a variety of tumor types. And to date I think we're close to about 500 patients with a variety of solid tumors that have been accrued to this study, this C-800-01 phase 1 trial. This paper reports on the sarcoma patients that were enrolled as part of this study. And so, again, given what I've told you about sarcomas being really immune cold, we were just so excited to have the opportunity to enroll on a next generation immune therapy for these tumors that really we were running into roadblocks trying to use immunotherapy previously. Shannon Westin: It's a very compelling idea and I'm so excited for you to tell people what you found. I think first things first, it was an early phase trial. So why don't we talk a little bit about the safety of the regimen. Was there anything that you didn't expect? Dr. Breelyn Wilky: Right. So similar to other checkpoint inhibitors, you know, the idea is that these drugs can cause immune mediated toxicities, right? So essentially you're revving up the immune system and it can sometimes get a bit confused and start attacking our normal cells, our normal organs, leading to essentially any number of toxicities of basically head to toe, something can get inflamed and you can develop a toxicity from that. So the key take homes with this particular drug with, botensilimab with balstilimab, we saw colitis was sort of the primary immune mediated toxicity and it was about a third of patients, give or take. It happens and it can be aggressive and needs to be managed aggressively. And you know, one of the things that we learned very quickly taking part in this study is how important it is that as soon as patients start to get diarrhea, immunosuppression gets on board. So steroids, early use of TNF alpha blockade, so infliximab for example, if we jumped on it quickly and we recognized it and we got the patients treated, it would resolve fairly quickly and even some patients could remain on treatment. So I think that was sort of the first take home is “Okay if you get colitis, you treat it fast, you treat it early and you can still have patients not only recover, which essentially everybody recovered from this colitis and then being able to continue on treatment and still have their anti-tumor responses.” So that's the first point. The second thing that was really interesting is part of the engineering of botensilimab on the back end of the molecule, it's been designed to decrease complement binding and it's thought that that triggers some of these other toxicities that we've seen with prior CTLA-4 inhibitors like pneumonitis or hypophysitis. We actually don't see that with botensilimab. So there's sort of this selective toxicity that may reflect the design of the molecule. But overall the treatment was, we didn't see any new safety signals that were outside of what we would expect in class. And colitis was sort of the dominant thing that we had to be ready for and ready to manage. Shannon Westin: We've been doing it for a while now, so we kind of know what to do and we can act quickly and really try to mitigate and avoid some of the major toxicities. So that's great that that was what was reflected in what you found. And then of course I think: What about the efficacy?” Right. This is what we care about as practitioners, as patients. Does it work and are there any subtypes that seem to benefit the most from this combination? Dr. Breelyn Wilky: Right. So for the sarcoma patients, we treated 64 patients and 52 of those patients were evaluable for efficacy. So a decent size group of patients in sarcomas, where, you know, typically our trials are pretty small, they're very rare, but we had 52 evaluable with at least one post baseline scan. So that was our criteria. And basically we saw across all of the patients, and keep in mind, these are heavily pre-treated patients, as you mentioned, so a median of 3 prior lines of therapy, so most of these patients had had chemotherapies and then about 20% had also had prior immunotherapy as well. So PD-1 treatments or so on. The overall response rate by RECIST was 19.2% for all of the evaluable patients. And then with iRECIST, which is sort of that immune adapted response criteria that allows for early pseudo progression, we actually had another patient who did have that. And so that response rate was 21.2%. Overall, we were really excited to see this in a heavily pre-treated group of patients. But what was really exciting to me was when we looked at the subset of patients that had angiosarcoma, that blood vessel tumor I was talking about earlier with my other patient. So angios come in two flavors. One is this sort of cutaneous type, or meaning involving the skin that has a UV signature, a UV damage signature, very similar to melanoma. So these tumors tend to have a high mutation burden. And oftentimes there is a track record that we've seen responses with immunotherapy in cutaneous angiosarcomas. But the other group that we deal with is called visceral angiosarcomas. And so these are totally different biologically. These are often driven by mutations in MYC or KDR amplification, and they arise in organs, so primary breast angiosarcoma, not associated with radiation, or they can arise in the liver or the spleen or an extremity. So these are very, very different tumors, and the visceral ones almost never historically have responded to checkpoint inhibitors. So we had 18 patients with angio split - 9 with cutaneous, 9 with visceral. And we were just blown away because the response rate for that group was 27.8%. And if you looked at the responses between the hot ones and the cold ones, it was almost equal and a little bit better in the visceral. So we had a 33% response rate in visceral angiosarcoma, which is crazy, historically speaking, and about 20% again in the cutaneous angios. So for a disease where visceral angio gets treated with chemotherapy, might respond initially, but then rapidly progresses - like these people go through multiple lines of therapy - to have a third of patients responding, and then some of those responses were durable. Our median duration of response for the study was 21.7 months, which is just nuts for sarcomas where we just don't see those sorts of long term benefits with the drugs that we have. So I think those are kind of the two main things. There were other subtypes that had clinical benefit and responses as well in d-diff liposarcoma, soft tissue leiomyosarcoma, which are again thought to be fairly cold immune subtypes. So just really exciting to kind of see responses we hadn't expected in a very challenging group of tumors. Shannon Westin: We see all these patients and we have patients that respond so well to immunotherapy with other histotypes. And so it's so exciting to see an option for these really hard to treat tumors that our patients struggle with. So this is so, so very exciting. I wanted to make mention, you know, I was really impressed with the amount of translational work you were able to do in this early phase study. So do you want to review just maybe a few of the key findings that you guys discovered? Dr. Breelyn Wilky: It's always great. I'm a translational researcher at heart and we do a lot of immune correlative work. And I think the reason I got so excited about this field to begin with was trying to learn why it works for some patients and why it doesn't work for other patients. So I'm a huge believer in learning from every patient that we can. So it's such a testament to the company, Agenus, who sponsored this trial to invest their time and resources into correlative studies at this phase. It's huge. So we learned a couple of things. IL-6 or interleukin 6 is a cytokine that basically has, in other tumor types, been associated with worse outcomes. And what we were interested in this group is we saw the same thing. And again, sarcomas have very, very little correlative biology that's done. We're really in infancy and understanding the microenvironment and how that milieu balances out in our tumors. So we were really excited to see again that lower peripheral interleukin 6 associated with improved overall survival. So again, kind of sorting out a group of patients that might be immunologically favorable when it comes to this type of therapy. The other thing that's important to know about sarcoma is so the other tumor types are lucky and have PD-L1 expression and the tumor is a biomarker, but we never have PD-L1 expression. We can find it in sarcomas and it can be loosely correlated with a chance of benefit with immunotherapy. But I've had patients respond that were PD-L1 negative, and I've had patients that were loaded with PD-L1 that didn't seem to make a difference. And that's not just in this study. So we saw in this trial a trend towards improved overall survival with PD-L1 expression that wasn't significant, but there was like this trend. And it's really interesting because, again, this is largely a CTLA-4 directed therapy. And so what we wondered is if PD-L1 expression is an index of sort of this underlying potential immunogenicity. And actually PD-1 works very late in the whole immune process. That's really at the very end where you've got the T cell that's facing the tumor cell and it's just activating that T cell that's already grown up and already educated and ready to go. Whereas CTLA-4 is really educating in early immune responses and expanding the T cells that have potential to kill. So I'm interested to look into this in more depth in the future to see if this is actually the biomarker for CTLA-4 directed therapy that we've been looking for, because we really don't have a great sense about that. And then the last piece just to note is that in this trial, like most others, very, very few sarcomas had high mutational burden. Everybody was very low, which reflects the population. And it's just really more encouragement than an immune cold tumor with very crappy neoantigens can still respond to immunotherapy if we get them the right agents. Shannon Westin: Yeah, I mean, I'm taking notes because we have such a struggle with this across the gynecologic tumors. I'm like, “Okay, maybe this is finally it.” So hopefully your work will go on to really inspire us across a number of solid tumors that have been traditionally cold. So, so very exciting. And I would just say for my last question, obviously, congratulations on this successful study. What do you think are the next steps for this combination in sarcomas? Dr. Breelyn Wilky: So, again, just to your point, this trial enrolled a bunch of different subtypes, and sarcomas are not the only immune cold tumor that this combo has looked really promising for, microsatellite stable colorectal cancer, ovarian cancer that was platinum refractory, non-small cell lungs. So I think the future is really bright for immune cold tumors kind of across the board. So, yes, lots of hope for not just sarcomas but in terms of our patients, I just have to be so grateful to Agenus for their interest in a rare disease. Sometimes it's hard to get that interest for a very challenging group of patients that are all heterogeneous, they are not all the same and our big clinical trials are a few hundred patients. It's just a very different environment. But they have been so supportive and involved in making sure that sarcomas are represented in their priorities. So there are ongoing discussions about what the optimal way to explore this further in sarcomas is going to be and I cannot wait to have the official plans in place. But my hope is this will not be the last that we see of these drugs for our patients. Shannon Westin: Well, I support that and my vote is on your side. So, thank you so much again, Dr. Wilky. This time just flew by. This was such a great discussion and I mean, I think it's, again, a testament to your exciting data. And thank you to all of our listeners. This has been JCO After Hours' discussion of “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas,” published in the JCO on January 27, 2025. So be sure to check out the full manuscript. And we hope that you enjoyed this podcast. And if you want to hear more about research published in the JCO, check this out on our ASCO JCO website or wherever you get your podcasts. Have an awesome day.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Dr. Wilky Disclosures  Consulting or Advisory Role: SpringWorks Therapeutics, Deciphera, Epizyme, Adcendo, Polaris, Boehringer Ingelheim, AADi, InhibRx Research Funding: Exelixis Travel, Accommodations, Expenses: Agenus    

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