A Comprehensive Overview of Tumor-Infiltrating Lymphocyte (TIL) Therapy for Metastatic Melanoma
Originally Broadcast: Tuesday, April 9, 2024 5:30 - 6:30 PM EDT
On the heels of the FDA’s approval of AMTAGIV (lifileucel) for unresectable or metastatic melanoma, join subject matter experts from Roswell Park for a comprehensive provider education event. They will offer background information and an overview on the new treatment protocols, discuss best practices when identifying potential patients and will host an interactive question and answer period to help provide insight on this exciting new option for your patients. Don’t miss this chance to discuss the latest adoptive cell therapy with some of the physicians who took part in the ground breaking research that made TIL therapy possible.
Moderator
Professor of Medicine
Chief, Blood and Marrow Transplantation Selection
Department of Medicine
Presenters
Professor of Oncology
Senior Vice President, Clinical Investigation
The Judith and Stanford Lipsey Endowed Chair in Clinical Cancer Research
Director, Center for Early Phase Clinical Trials
Chief, Early Phase Clinical Trials Division
Chief, Melanoma Section
Department of Medicine
Associate Professor of Oncology
Department of Medicine
Associate Director of Early Phase Clinical Trials for Solid Tumor Cell Therapies
Good evening everyone. My name is Shanan Holton. I'm a blood marrow transplant physician at Roswell Park Comprehensive Cancer Center here in Buffalo New York. Something that I've told my patients for over 20 years is that the cure of cancer always has to involve the immune system when we're dealing with cancer. And we give chemotherapy some of the recovery of the immune system after chemotherapy is therapeutic, it helps to control the cancer. We've known this for decades, but we didn't always have ways to harness the immune system. We just had to hope that it would recover and control the cancer. Over the decades, we've developed different molecules that can help stimulate the immune response. But in some patients, that's not enough. What we have developed over the most recent era is actually the ability to give immune cells themselves to help treat the cancer. And what we'll be talking about tonight is a really incredible innovation that is going to be of benefit for patients with solid tumors. This is so different because the majority of therapies in this space have been develop for hematologic malignancies or cancer of the blood and bone marrow. This represents a really novel breakthrough in our field. It gives me great pleasure to welcome you all to tonight's educational event entitled, a comprehensive overview of Till Therapy for Metastatic Melanoma. I'm looking forward to serving as your moderator for the evening. We have two excellent presentations prepared by experts in their field. We will hear first from Dr Anuradha Krishna Murthy, the Associate director of early phase clinical Trials for solid tumor cell therapies. From there. We will join Dr Igor Puzo, who serves as the Vice President of Clinical Investigation, as well as the Chief of our Melanoma section. Both physicians have worked extensively with this therapy prior to the FD A's recent approval and are excited to speak to its merits. Both talks will be presented sequentially with a live question and answer period to follow. I encourage you to submit your questions at any time during the program as they will be collected and reviewed with the experts following the presentations. As always, we at Roswell Park appreciate the opportunity to produce these educational series as a means to connect with our peers in the community as well as our colleagues at other institutions. Our hope is that you find this program informative and that you please pass along any feedback. When prompted. My name is Anu Krishnamurti. I'm the associate director of Early Phase Clinical Trials in Solid tumor cell therapies. I am involved in the G I division, the early phase clinical trials division and in the solid tumor cell therapy division here at Roswell Park. I will be talking to you about tumor cell therapies today, particularly focusing in on tail therapies. I don't have any um disclosures to give you a broad overview and the immune system comprises of the innate immune system as well as the adaptive immune system. The cells in the blue comprise of the innate immune cells versus the cells in the brown comprise of the adaptive immune system. Here we will focus uh on T cells, particularly helper T cells and cytotoxic T cells along with the antibodies. Uh because this talk focuses in, focuses on T cell therapies. Immune surveillance is driven by T cell activation and regulation. Cytotoxic T cells recognize antigens presented by antigen presenting cells through MH C one activated cytotoxic T cells will bind to antigens in foreign or abnormal cells such as tumor cells resulting in cell death. T helper cells recognize antigens presented by antigen presenting cells or apcs through MC. Two T helper cells will activate B cells and cytotoxic T cells and secrete cytokines who inform other cells about the pathogenic threat. T cell regulation is also an important part of immune surveillance. Myeloid ripe suppressor cells inhibit T cell responses by mechanisms that include nutrient sequestration, reactive oxygen species generation and interference with trafficking to abnormal cells. So these regulatory T cells can suppress active or inactive cytotoxic T cells and um T helper cells or even antigen presenting cells. T cells um bind to antigens on the surface of foreign or abnormal cells um through the T uh TCR MH C one complex. As you can see in the image upon recognition um by the cytotoxic T cells of a foreign or abnormal cell, cytotoxic T cells produce pins and graz IMEs. These Perin form pores in the plasma membrane of the foreign or abnormal cells. Grandys enter through the pores, break down proteins and lies the cell. Uh mutations in tumor DNA cause changes in tumor protein sequences that can be recognized by the immune system as a tumor associated antigen. So, let's talk a little bit about how T cells um can detect and eliminate tumor cells. This is usually done through uh the process of neo antigen recognition. Tumor mutations result in tumor specific antigens or TS A that can activate the adaptive immune response. So you can see those antigens on those tumor cells right there. Dendritic cells. Um A type of antigen presenting cells can recognize neo antigens and activate cytotoxic T cells through antigen presentation to T helper cells. Um Il two secretion supports the proliferation and clonal expansion of activated T cells. These activated cytotoxic T cells migrate into the tumor micro environment um where it finds these tumor cells and then results, this results in um tumor cell death. Completion of immune surveillance destroys tumors before they become clinically apparent. One's tumor infiltrating lymphocytes or tills are in the tumor micro environment, they bind to neo antigens presented by the tumor in mec resulting in perforin and grandy mediated tumor lysis. Right. Now, we just finished talking about how tills affect the tumor micro environment. Now, we'll talk about how tumors can modify their own micro environment to suppress the activity of tills or tumor infiltrating lymphocytes. Tumors engage immune suppressive mechanisms that lead to dysfunctional or fewer tills in the micro environment um which prevents tumor cell death. So, one of the first ways in which this can happen is by loss of expression of those antigens that we talked about or reduction of MH CS, enabling tumor cells to not be detected. Suppression of cytotoxic T cells and T helper cells via those T regulatory cells that we talked about earlier. Um reduces immune surveillance as well. Release of certain cytokines can result in uh immature dendritic cells in the tumor micro environment. And these do not present antigens to T cells. And therefore, these T cells do not destroy those tumor cells in that environment. Macrophage inhibition of T helper cells also reduces immune surveillance. The other way in which tumors can modify the tumor microenvironment is by up regulating immune checkpoint molecules and reducing the potential of tills to eliminate tumors. Suppression of tumor infiltrating lymphocyte activity in the tumor micro environment, facilitates tumor growth and development of cancer. So, in summary, foreign or abnormal cells or tumor cells are eliminated through immune surveillance using innate and adaptive immune systems. T cells recognize antigens on the surface of foreign or abnormal cells including tumors and are activated and regulated by other cells in the immune system. T cells in the tumor microenvironment that bind to tumor specific antigens or T SAS are called tilts. Tumor infiltrating lymphocytes. Tumor cells can suppress the activity of tills by inhibiting immune cells in the tumor micro environment or up regulating of immune checkpoint molecules. So now let's look a little bit at the evolution of immunotherapy. The immune system has been harnessed um especially in the last 30 to 40 years for the treatment of cancer. Um There are many different ways in which the immune system can be harnessed. Um The most famous or well known of these are the checkpoint inhibitors where there's inhibition of PD one PDL one or CTL A four with monoclonal antibodies that enable T cell mediated tumor regression. Other um well-known immune therapies include car T cell therapies where the peripheral blood um T cells are removed. Um and um they are modified to express uh chimeric antigen receptors um that recognize tumor antigens. Uh Other well studied re or researched immunotherapies include cancer vaccines, um cytokines, um oncolytic viral therapies, um TCR engineered T cells and last but not the least tills or tumor infiltrating lymphocyte therapy where autologous tills are expanded um outside of the body and reintroduced in patients for tumor elimination. Uh This um slide shows us the milestones in cancer immunotherapy. And um you know, it's amazing to see the the extent of time it has taken for all of these uh therapies to be developed. The first dendritic cell or A PC was discovered in the 19 seventies. Um The T cell receptor was discovered in the 19 eighties I two was approved for renal cell carcinoma and melanoma in the United States. In the 19 nineties. The first report of clinical efficacy of tills in metastatic Melanoma, which was done by Doctor Steve Rosenberg and his colleagues was reported in 1994. Um from that point on, there have been multiple innovations and multiple um milestones where we have definitely improved survival for patients. Um You can see the first checkpoint inhibitor, the anti CTL A four monoclonal antibody was approved somewhere around the 2011 to 15 time frame for advanced melanoma, which was followed very quickly by the anti PD one monoclonal antibodies. These therapies have definitely changed the landscape of Melanoma treatment. Um And at present, um there are multiple different types of therapies that are being looked at. And uh most recently in February 2024 we had the approval of Lil lil or uh which is a uh tilt therapy for Melanoma. Um just because checkpoint inhibition is so well known and um really well used in Melanoma. I wanted to quickly touch on this topic. Um So, engagement of checkpoint pathways aid and tumor evasion of tumor infiltrating lymphocytes binding of PDL 12 PD, one counteracts um TCR signaling and changes T metabolism and it results ultimately in till death. Um binding of CTL A 42 CD, 8086 inhibits till activation and proliferation by disrupting the interaction of tills with A P CS. Um immunotherapy with checkpoint inhibitors activates T cells within the tumor micro environment. So, here we can see that um the anti CTL A four antibody um inhibits the CTL A four CD A T 86 access between A P CS and T cells. Um with anti CTL A four antibodies leading to T cell activation and tumor cell elimination. Um PD one PDL one inhibition um with anti PD one monoclonal antibodies such as nivolumab embolism Selim of dosa or dosel or anti PDL one, a monoclonal antibodies such as a TZO A Tizol Liz Doval or a velum um inhibits the PD one PDL one axis between tumor cells and T cells. Um with that leading to T cell activation and tumor cell elimination. I wanted to show you the trends in immunotherapy drug development. There's been a growing interest in cell therapies, as you can see by the graph here. So, adoptive cell transfer immunotherapy introduces autologous or genetically modified T cells into the tumor micro environment. The two big groups are tail cell therapy versus TCR or car T cell therapy. Um in terms of um TCR or car T cell therapy, peripheral blood T cells are isolated, they are transducer, um T cells with uh viral vectors. And then um as far as car t cell therapy is concerned, these T cells have been genetically engineered with cars or chimeric antigen receptors. Um for mec independent antigen recognition TCR cell therapy. On the other hand, um is um RT cells with genetically modified TCRS that uh involve mec dependent antigen recognition tail cell therapy. On the other hand involves tumor resection where um a piece of the tumor is resected and um tumor infiltrating lymphocytes are isolated in vitro. Um and then they are um expanded in vitro and then um given back into the patient um for um activity against um tumors. So, in terms of tail cell therapy, um solid tumors present a wide array of um tumor specific antigens. Yet fewer than 1% of tumor specific antigens are shared across patients with certain solid tumors. T cell therapy has the potential to overcome um challenges that make car T cell and TCR therapy impractical and solid tumors including delivery of car T cells or TCR modified T cells into the tumor micro environment, immune suppression of car T cells or TCR modified T cells in the tumor micro environment, lack of heterogeneous tumor specific antigen expression in all tumor cells and incidence of CRS and other autoimmune adverse events with car T cells and TCR modified T cells that are not seen with tilt therapy. Um The most important takeaway from all of this is that in till cell therapy um in solid tumors, the tills are polyclonal and they recognize a multitude of an individual's tumor specific antigens. This chart here provides us with um the differences in um the various adoptive cell transfer um immunotherapy uh mechanisms till therapies. Um As I mentioned earlier, their target is tumor specific antigens um for car therapies. Uh The target is non MH C based cell surface proteins. Whereas for TCR cell therapies, it is MH C peptide complexes till um specificity is polyclonal versus car and TCR, the specificity is monoclonal um in terms of production um til therapies uh once uh it is isolated from the tumor and expanded X vivo um in terms of car therapies, the isolation is from the peripheral blood and where um once these T cells are isolated, they are trans and expanded ex vivo. And um the same is true for TCR based therapies in terms of the main toxicity, as I mentioned earlier. Um the toxicities for tills are related to lympho depletion and um io two. So the chemotherapies that I use for lympho depletion are the reason for the side effects that patients experience during uh the lympho depletion depletion phase of their treatment. Um And um the IL two based um side effects are what patients usually experience when we give them IL two for um uh T cell proliferation in car therapies as well as TCR therapies. Um Another added uh toxicity is that of cite a kind release syndrome which is not seen with til therapies till therapies um have recently been approved. So Lil Lil has been approved for advanced Melanoma. Um in February 2024 car therapies have been approved for um many hematologic malignancies such as A LL and BC LTCR therapies are um currently being researched and um hold a lot of potential for um solid tumors but um work is still in progress. So, in summary, the immune system can be harnessed for the treatment of cancer through adoptive cell transfer and other immunotherapies, immunotherapy with checkpoint inhibitors activates T cells within the tumor micro environment. Adoptive cell transfer, immunotherapy introduces autologous or genetically modified T cells into the tumor micro environment. There are three types of adaptive cell transfer immunotherapy in till cell therapy. Tills are isolated from the tumor microenvironment grown in vitro and transferred to the same patient after lympho depletion in TCR or car T cell therapies. Peral blood T cells are isolated transducer with TCR or car grown in vitro and transferred to the same patient after lympho deletion. So let's get into a little bit more about tail cell therapy mechanism of action and treatment process tills bind to many uh tumor specific antigens and cause tumor cell death. Tumor specific antigen presentation via A PC and then a PC migration from the tumor micro environment um to the lymphoid organ takes place in the lymphoid organs. The A P CS prime naive T cells to respond to an array of tumor specific antigens. Tumor infiltrating lymphocytes bind to many tumors specific antigens and cause tumor cell death. Tumor specific antigens are presented via antigen presenting cells. These antigen presenting cells migrate from the tumor micro environment to lymphoid organs. The A P CS prime, the naive T cells found in the lymphoid organs uh to respond to an array of tumor specific antigens. These polyclonal T cells in turn, migrate to the tumor microenvironment. Here they bind to tumor specific antigens and cause tumor cell death through perforin and grandy mediated um destruction of tumor cells. These are the various stages of tail cell therapy. The very first step is tumor tissue procurement. Um This is what we use to produce the tills, the till production um happens by expanding it in vitro, preparative lympho depletion regimen is given to the patient. Um while the T cells are being expanded in vitro, these tills are then infused um into the patient. Ielt two is administered to the patient and then um the patient is discharged from hospital after recovery. So, tumor tissue procurement, the objective of this is to procure viable solid tumor tissue uh which has a um good representation of tills that is found in the tumor micro environment. The considerations here are that we should have sufficient tumor sample of appropriate quality for till production. And also we need to use an aseptic technique to limit contamination. Tilts are produced in vitro with the procured tumor tissue in vitro expansion of tumor tissue with il two enriches the till content in the sample tills are grown and amplified with uh the appropriate methods. Um And then these tills are expanded with a rapid expansion protocol to rejuvenate and amplify the till numbers in the billions. These tills are cryo preserved and then shipped to the institution that the patient is admitted in and prepared for infusion. Patients are lympho deleted before till administration. The objective of this is to reduce the myeloid derived suppressor cells and the tumor associated dendritic cell activity that limits the anti tumor effect of tills and eliminates T cells from the host to decrease the cytokine zinc lympho depletion has enhanced the antitumor effects of tills in mura models with a direct relationship between the extent of lympho depletion and the magnitude of the antitumor effect of transfer tills. After lympho depletion, patients are infused with tills followed by il two infusion. It is a one time infusion of autologous tills, uh polyclonal tills that recognize tumor specific antigens that are patient specific are infused. Uh a short course of high dose il two is given which supports T cell activity. Um Once the patient recovers from um any side effects related um to these treatments and the patient is um assessed to ensure that um they have normal blood cell counts and they are feeling clinically well before leaving the hospital. So in summary, tumor cell that's mediated by tills involve presentation of multiple tumors specific antigens by A P CS A PC priming on naive T cells with multiple tumors specific antigens. T cells primed with multiple tumors. Specific antigens enter the tumor micro environment, bind to different T SAS and cause tumor cell death by releasing perf and graz T. Cell therapy involves tumor tissue procurement, um till production in vitro prepa uh preparative lympho depletion, infusion of tills il two administration and then recovery and discharge lil lil or am tag. V is the first FDA approved till therapy for patients with advanced melanoma who have been previously treated with at least one systemic therapy. The accelerated approval was based on clinical trial findings sponsored by Ivan Therapeutics that showed improvement in objective response rates and duration of response. The side effect profile was also found to be tolerable. This is the first cellular therapy to be approved in a solid tumor. This provides a lot of hope um because um this these still therapies can hopefully be um expanded to other solid tumors in the future. So what comes next? Combination of tills with other immunotherapy drugs such as checkpoint inhibitors? Um These trials are already ongoing and hopefully will provide us with some uh promising results. Use of tilts in other solid tumors such as advanced lung cancer and designing tills that are better targeted. All of these are um great um uh treatment, potential treatment options to look forward to. Thank you for watching this presentation. I will be happy to answer any questions at the end of this program. Hello, I'm Igor Puzzo, Director of Center for Early Clinical Trials and Chief of Melanoma Division at the Roswell Park, uh Comprehensive Cancer Center in uh Buffalo, New York. And today I will share with you data on tumor infiltrating lymphocyte cell therapy in Melanoma, Melanoma, one of the most immunogenic of all cancers uh underwent a complete revolution in the last 1015 years. Uh We went from overall survival between 6 to 10 months to uh 50% overall survival of 72 months, which is six years. Uh According to the American Cancer Society data of 2022. Uh we now have 7000, 700 people dying from Melanoma while we used to have 15,000. Uh but many patients progress on immune checkpoint inhibitors by 12 to 18 months. And I after they had their anti PD one anti CTL A four therapy and a combination of uh inhibitors of breath meg. Uh There are limited options to them. Uh As you can see, adaptive cell therapy is uh not a new therapy. It's a technical approach in which the patients autologous T cells are expanded, manipulated ex and then re infused into the patient to exert an anti tumor response. And uh the drug which was recently approved Leilo is an autologous, centrally manufactured tumor infiltrated lymphocyte product approved by FDA for treatment of patients with unresectable metastatic melanoma who progress on anti PD one therapy and if applicable on a breath me therapy as well. Um You know, the tumor infiltrated lymphocytes, they are isolated from the tumor where they were activated against myriad of tumor, uh specific antigens, the neo antigens. Uh A lot of people talk about and try to create vaccines against. Um You can see uh we are trying to take out these cells and activate them and then reinfuse them so they can exert their something is preventing, preventing the cells to kill the tumor, although they are able to get into the tumor. So uh this is the timeline. It will give you an idea how old uh this therapy or the idea for this therapy is uh some of the first uh trials were done in the eighties uh by the pioneer in the field, Dr Steven Rosenberg and NC I and finally, in 2020 before we have approval of uh Leo. So um it is the first uh therapy of such sort and uh it has been approved in February of 2022 and 24. And it's the first uh tumor cell uh therapy or cell therapy for solid tumors um uh ever uh approved uh in this indication. Uh the stages, uh my colleague uh talked about it before uh we need to remove the tumor from the patient at least 1.5 centimeter uh at length, uh produce uh the tills uh in a central facility. Uh prepare the patient with lympho depletion regimen, reinfuse the tail cells, then give a couple of doses of in interleukin to to help these cells survive and thrive and then we see the patient recover and hopefully respond. Um So, uh the clinical trial which led to the approval was the phase two clinical trial with 178 participants, they were all adults with unresectable or metastatic Melanoma. They had the uh preparation exactly as I uh uh described. And uh they were uh uh there were three arms in the trial. They were nonrandom mines. The first arm was no cop preserved. Leo, the second one was cryo preserved and the, and the third one was again cop preserve, Leilo uh to confirm uh the second uh uh cohort data. So, uh the important thing to note about the till therapy, it's a one time uh till uh it's a one time therapy. So, although uh the patient has to go through a certain process, uh it's only for one time and if they respond, uh as you will see, they respond for a long time. Uh the uh pool data were uh considered uh due to identical eligibility manufacturing process and central response assessment. Why it was really important because the trial didn't have control arm to have a long enough uh outcomes and follow up as well as have two independent cohorts to be able to glean if there were um all the conditions uh uh well balanced. Uh the inclusion, typical inclusion uh patients uh good performance status. They had to progress on immunotherapy. Uh Of note, 50% of those patients underwent therapy with uh uh uh the PD one and CTL A four checkpoint inhibitor therapy. This is the largest trial in such a cohort and the patients with breast mute patient had to have a breast mag inhibitor therapy as well. Uh The exclusion uveal ocular melanoma were not uh included hypersensitivity, heart failure, you know, other conditions and no bridging therapy was per permitted between tumor resection and leilo infusion. Uh The for the manufacturing purposes, uh the tumor removed had to be more than 1.5 centimeter, less than four centimeter in aggregate diameter. Some patients had more than one tumor uh site removed. Uh The uh samples were trimmed, sent to the GMP central facility. And about 22 days later, a cryo preserve the infusion was created uh and a patient was prepared with the Noyo ala lympho depletion uh followed by single l infusion. An abbreviated course of high dose interleukin two, only up to six doses of interleukin two were administered. While the typical high dose Ikin uh two treatment we are all familiar with included for up to 14 doses two times in a row. So it's uh six or less versus 28 or less. A very different situation. And uh the, the treatment was feasible. As you can see, out of the 189 patients uh enrolled 100 56 received leilo and uh 100 53 received leilo or were analyzed for efficacy. As you can see, some patients either progressed or uh didn't have a success with manufacturing but only 4.2% there. Uh Some uh patients uh got different treatment with your consent. Uh Nothing really sticks out as a big problem, you know, there. And uh most of the patients uh receive the li in 95 plus percent uh to specification. And uh here are the results. So you can see characteristics uh heavily pre patients mostly. Um uh most of them got uh both CTL A four and anti PD one. Some of them even got high dose IL two, about 10%. And uh as you can see uh most of the sites removed, you know, for the uh for the tail production were either lymph node or skin or subcutaneous tissues, not surprised there, but also visceral organs or others uh were utilized. And uh there was really no difference in the success rate of these. And uh here you see cohort two, cohort four and the pool analysis. Uh I will point to you the pool analysis where we have a 31.3% combined cr pr uh And with a stable disease in another 46.4% of patients. Uh ie uh clinical benefit. Um well, over 77% which is really good for this power of type of patient and a long term follow up satisfying all the uh necessary needs to see long term survivors. From this data. You see deep responses. Uh 78.6% patients had reduction of target lesions. Uh You see the median time from l infusion to best response, quick 1.5 months. Uh 81.3% responders achieved IRC assessed response at the time of first response assessment. So not only is the one time and done treatment but also the outcome can be read very, very quickly. And uh uh there were deepening of some of the responses, six patients with initially partial response eventually achieve the complete response. And uh 10 patients, 20.8% improved from stable disease to pr which is exactly what one wants to see with immunotherapy. Uh The response was observed across all subgroups regardless of age prior anti CTL A four use breast mutation status PDL one status. And even in mucosal and nonm mucosal subsets, the mucosal is important because that's area of unmet need. These patients uh do poorly with anti PD one alone. And uh uh what stick out as a good prognosis uh for these patients having a good performance status by icon uh having a uh uh normal L DH and uh having a target less than median, uh uh if you had all three, you had much better chance to respond. And uh this is not surprising, confirms data from our uh uh prior papers with uh you know, looking into as well uh durable responses as you can see, uh median duration was not reached. And uh uh 60% plus patients uh had a response when they achieved response initially. And um this is really important because again, it's immunotherapy. And when we do immunotherapies, we wanna see durable responses uh overall survival again, you know, um uh the long term overall survival somewhere around where the uh the response rate is 30% but a 12 months, 54%. Again, after progression on uh all the other um uh treatments which uh is extremely uh uh promising. And uh then by response status patients who responded uh had a better survival of 60% at the year 45. And uh and uh the patients who didn't respond, you can see had a much less chance of surviving uh long term uh progression free survival. Again, we see a plateau associated with uh uh immune mediated responses and uh the adverse events are important. So, uh this is a treatment which should be done in a specialized center. Uh with a certified team, there is a special process to go through certification and um the warning included uh with this uh treatment includes uh treatment related mortality, prolonged severe cytopenia, severe infection, cardiopulmonary and renal impairment. Uh important to know uh that 7.5% of patients uh had a treatment related death uh with this treatment. So again, if one is attempting to do this treatment, it is of utmost importance to do it in a certified center with multidisciplinary team available, trained and certified. Well, where do we go from here? Uh uh So, for example, uh we have enrolled patients here with prior checkpoint inhibitor therapy, but some of the data in the lab uh as well as some of the front line data now uh presented by Doctor uh Diva Carava from UP MC suggest that maybe uh using the front line or in combination front line would be even more efficacious. So, uh uh there is a prospective randomized trial in metastatic melanoma uh plus minus pembrolizumab underway uh to actually confirm uh this uh hypothesis. Um What about um using T which can produce their own cytokine ie decreasing the need for uh additional INL look into infusions. Now, there are now uh uh efforts uh such as Oobxx 115, a novel engineer tills uh which can actually produce membrane bound IL 15 under development. And then obviously, uh can we expect use to other tumor types such as cervical cancer underway, non small cell lung cancer, head and echo squamous cell carcinoma all underway. And uh uh always a question whether uh we can decrease toxicities by potentially using less of the chemotherapy preparation regimen. So, in conclusion, we now have the first FDA approved uh adaptive cell therapy option for patients whose melanoma progress on anti PD one and if applicable breast m targeted therapy in the current phase two trial, including 1, 53 patients enrolled in two consecutive cohorts one time leilo uh using crowd preserve products demonstrated Orr of 31.4% and median dor was not reached at a median study. Follow up of 27.6 months. This is a marked improvement over the therapies available for patients in the post. The checkpoint inhibitor setting excellent durability and deep responses over time. Even deepening over time, favorable clinical characteristics of lower tumor burden, uh low target lesion of a median uh diameter normal L DH are associated with greater likelihood of response. So we should start thinking all, start thinking about io uh till therapy at the time of patients starting first line immunotherapy with checkpoints to be ready with this uh treatment. If patient uh turns out to be a checkpoint progressor and our team at Russo Park is ready and willing to help. Thank you very much. Hi, everyone. Welcome to the live question and answer session. So happy that you're joining us tonight. Um Before we get started with the questions, I just want to emphasize that we want to hear from you and so please leave your, your questions in the chat and we'll get to them. I know there's a lot of exciting things we want to talk about tonight, but we want to hear from you. So please uh leave your questions for us. And now have you introduced yourself? Hi, my name is um Anuradha Krishna Murthy. I am one of the medical oncologists working here at Roswell Park. Um I, one of my areas of expertise is tilt therapy. So I will be seeing a lot of the patients who get referred here for um tilt therapies here. And I'm Igor Kano, I'm the chief of Melanoma and uh I also lead a phase one group and uh I have been involved with uh pill therapy development since 2016. So thank you so much for watching our program. Yeah, and Sharan Holton, chief of BMT. So this is really a a fascinating intersection of cell therapy, immunotherapy solid tumors, the the first FDA approval in this space. So, Doctor Christian Murphy, what do you think this means for our field? Um It's particularly exciting because um there have been years of work behind all of this and solid tumors is a particularly difficult space. So the fact that we have a TL therapy that's now approved for solid tumors is very, very exciting. Yeah. What do you think it means going forward? I'm hoping that this will mean in the future that many other solid tumors will also have to therapies and uh patients will get great responses and sustained responses, which would mean a lot for certain, very difficult to treat cancers. Absolutely. I'm curious your thoughts. If you had to make a prediction, what type of solid tumor might be next? I think, given um the sequence of events that we have seen with checkpoint inhibitors and all the other immunotherapies, I think perhaps lung cancers is a very good um uh potential choice if we were to make a few guesses. Doctor Pozna, how do you explain this therapy to your patients? Well, t therapy is not a new therapy. You know, it's uh has been in development since the 19 eighties. And uh it is basically to use the uh patient's own cells which uh make it into the tumor. So we know that they actually tried to kill the tumor but they cannot. So we are releasing those still cells uh uh activating them outside of the patient's body and then putting them back to actually kill the tumor. Um How do you explain the process and the timeline, what does that sound like from the, the patient perspective? So the process, you know, the process needs to start, you know, uh at least uh intellectually very early. Uh because the timeline, you know, is not completely short, uh making of the tills itself takes about 22 days, but there is always the preparation time uh need for harvesting uh the tumor. Uh and then of course uh after the cells are ready uh infusion uh IO two and then uh uh the recovery. So I would say from the time we first meet the patient to the time when they are finally recovered about six weeks, how do you explain what it feels like when you're getting the till therapy in the aisle too? Well, you know, it's uh it's not as easy as therapy. You have to select your patients wisely. Um, you know, there are some black books warnings, you know, as, uh I have described in my talk and, uh, so these patients, you know, have to have a, uh a good performance status, you know, be able to move around freely. Uh, and, um, you know, be able to do some light work, chopping, cleaning, cooking, you know, that kind of situation. And, uh, uh, and how does that feel? Well, the, uh chemotherapy certainly will, uh cause them some, uh, uh fatigue, uh lower counts. You know, there could be the fever, you know, neutropenic fever. Uh, the cells themselves may cause, you know, some cytokine relief syndrome, which is usually limited and we have good standard operating procedures, you know, on how to manage them. And, uh, and then there is the uh interleukin two part, which actually is not as difficult as people think because what I think about is the uh high dose interleukin two therapy, which I have done, you know, 350 times. Uh over more than 10 years. And uh but that was designed to be uh interleukin two lo and uh that meant up to 14 doses twice in a week apart. This is up to six doses only once. And we actually know that as long as the patient gets two doses, the cells will survive. It's just to feed the cells, not kill the tumor. So uh the il two really adds very little if anything. It's more the chemotherapy and perhaps the cell infusion. I think that's a real important point, right? It's not like the high dose aisle two of yesteryear. Um I used to describe that to patients like, you know, you're trying to light a barbecue fire, you've got your briquettes, you put a little uh spark down there. Nothing much happens. Well, you get out the lighter fluid, squeeze it on and then all of a sudden you have a big flame. The A L two being the lighter fluid really making things very hot. But this, it sounds like it's not as intense as the very high dose IO two. That was the, the stand alone therapy. No, it is not, you know, by no means. And uh and we actually uh do not really push the doses. If patient has some toxicity, we can freely stop because we know that as long as they got at least two doses of IO two, you know, they are in the ballpark to respond, you know, no need to push any doses uh beyond that. And uh and uh if they tolerate it, you know, it still stops at six doses, not 14 and not twice in a row, but just right dose up to six doses that, you know, the goal of having two doses is that within a certain time frame, within the same day or within a span of several days, usually you can, you actually uh I'll time it every eight or every 12 hours, you know, 12 hours is easier for recovery and for administration. So I would say, you know, those one usually doesn't do much, you know, those two maybe, you know. So in the 24 hours, you got two doses. If the dose three is questionable, you can stop right there. Doctor Krishna Murthy, do you think there might be a time in the future when we use something other than IL two for this type of stimulation of whatever type of cell we're putting in to try to treat the tumor or will be we, will we be using IL two for a long time? Um So far all the studies have been done with IO two. There are other interleukins out there, some that actually uh promote uh t regulatory cells while the other ones promote the CD A T cells. So, um if with more research, perhaps we'll be able to uh use some other ielts uh interleukins out there that might, you know, be able to stimulate those T cells appropriately just for the what, what would be the problem with potentially stimulating the regulatory T cells as well. So, the regulatory T cells are what suppress the cytotoxic T cells, the stuff that kills the cancer cells. And so if we manage to stimulate the regulatory T cells, we would end up um suppressing the cytotoxic T cells and therefore suppressing the anti cancer activity. Exactly. So it would be nice to have something more specific that didn't have the potential to stimulate the, the counter regulatory mechanisms. Ok, great. Um Doctor Puzo, uh are there any types of conditions which would make a patient ineligible or who should not receive till therapy? Yeah. So I would say somebody, you know, with the poor performance status, you know, somebody who is wheelchair bound, you know, really uh cannot tolerate much of activity. Um you know, severe COPD uh in the high dose IO two E we actually tested pulmonary function test and uh we're aiming for uh fev one, you know, the ability to uh breathe out at least 1.5 L, you know, in a second. And then, you know, heart conditions, you know, uh inducible arrhythmias. Uh um you know, somebody who failed, you know, stress test, uh depressed left ventricle systolic function. These would be the patients I would not recommend, you know, to try, you know, severe uh renal insufficiency. Can you find that? What would be a cut off, do you think potentially of renal function? Yeah. So, I think, you know, the cut off would be probably 30 CCS per minute. Ok. And what about heart function? Yeah. For the heart function, I would say that uh uh left ventricle systolic function, you know, less than uh normal, you know, would be definitely uh uh risky. What about liver dysfunction? Especially if there's um metastatic disease involving the liver. Would there be any limitation there? I mean, that could be, you know, you, you, you know what we look at, you know, is the synthetic function of the liver. So, uh you know, normal album and normal uh coagulation test and uh and a normal bilirubin are important. Um you know, if they are affected, you know, that tells you the liver is affected, you know, the actual, you know, um a stalt alfa, you know, especially with uh uh metastasis. Um some people would say five times upper limit normal. Uh But uh you know, I think that's more uh that's more uh negotiable, but uh certainly uh somebody with uh uh bilirubin more than 1.5 times upper limit normal. I would not recommend uh the, the, the, the treatment. OK. Um One of the audience response questions was regarding CNS metastasis. Is there any contraindication if there's AC NS disease or is there a particular chance of response that there's CNS disease? Yeah. So at this point, you know, we would exclude anybody with active CNS disease. Uh So you have to have uh the CNS disease treated, you know, typically with teac radiation and stable for at least four weeks. So the second scan and uh there are studies. So uh uh one is uh going on at Stanford uh with Doctor Beth of Warner, uh specifically designed to look into the question of uh tills and uh CNS disease. So that would be a better avenue for those patients going to the study not to the standard treatment if they have unstable uh metastasis. OK, I see. Thank you. Um Doctor Christian Murphy, what do you think about age? Is there any age limit? Age is always such a difficult question? I think uh the performance status is more important, obviously, in all of the previous um trials, clinical trials that have been done patients over the age of 70 or 75 have been excluded. But um I don't know that age by itself is a cut off. I think um the patient's performance status comorbidities, those would be more relevant factors um to determine which patient would be an ideal candidate. I know you do a lot of work with different immunotherapies and cell therapies for solid tumors in your experience. What is the optimal uh way to do transitions of care? How do you collaborate with a multidisciplinary team here? We're involving surgeons and cell therapists, solid tumor oncologists. How, how does the team work together the best for the patient. I think um the best way to go about it actually is to actually have a plan right at the beginning, even before you start seeing your very first patient for any new therapy, have the systems in place and um have the right contacts in every uh area. So, you know, which surgeon is going to be doing the job, who's the medical oncologist, who's going to be involved, who's going to be doing the referrals, who's going to be um monitoring the patient um within the, as an inpatient at the hospital. And then also, of course, the nursing teams, all of those uh the pharmacists, they are all equally important in this process and they um we should know who the points of contact are. And once you have that system in place, which as we do at Roswell Park, um you know, once you have all of that in place, um it obviously becomes a lot easier to put the person through that flow of processes. Exactly. Uh Doctor Poff, is there a role for bridging chemotherapy? Say the surgery is performed, the tumors removed, the tills are being manufactured. Is there some role for debulking or any kind of treatment during that manufacturing process or? No, it depends, you know, if patient has a breath mutation, then certainly using uh a combination of uh targeted agents for breath meg, you know, would be what we would use. Uh If they don't, you know, it's more questionable because, uh, these patients will be progressing on a typically now, combination PD one CT A four or PD one leg three, which is a standard and, uh, trying to salvage them with, uh, a standard of care doublet, you know, has a response rate about 10 12%. And the risk of developing, uh, uh immune, uh related adverse event, you know, from that one dose, which is probably all you can uh get in those four weeks, uh are considerable and uh you probably will not see any response whatsoever from that. So for patients who do not have breath mutation, uh bridging is really futile, you end up taking potential risks that without real uh chance for benefits. So really low response rates, it's not worth the toxicity for most people unless there's a mutation where you can use a targeted agent. Yeah. Ok. Um Doctor Christian Murphy, when the patient comes in, receives their lympho depleting chemotherapy tills and il two. What's the typical amount of time a patient would expect to be cared for by cell therapy physicians? Um, typically we anticipate that they will be cared for for about 4 to 5 days um within that time frame, um eventually these patients will get discharged and may have one more visit to make sure everything is uh uh you know, well, the patient is well, clinically, there are no issues and then they would go back to seeing their melanoma physicians again transition back. Great. Uh Doctor Pzn, is there a role for maintenance therapy? This is a concept that's emerging in cell allogeneic cell transplantation. Say patients who have leukemia, who may have mutations such as those that are are t with drugs might go on maintenance therapies after the answer would be no at this point. Um you know, the, the the whole premise of the pills is one and done. So patients will get a therapy and three months later, they will get a scan if they responded, they responded. And uh you know, it should be durable. You know, as uh we have seen the data, 60% of these responses are durable and the ones who didn't respond, they will get the different treatment. How long do you wait before you determine success or failure of the therapy? Three months, three months, about three months, you know, the, so, you know, the calculating from the time people got ills, you know, that would be the day one, about three months. You know, obviously, if clearly you have no success and patient is progressing rapidly, you are not gonna wait three months, you're gonna scan them early, confirm that there is no response and uh and move on. Uh you know, we have seen from the trials that the time to response is about 1.7 months. So it's actually if it comes, it comes quickly, if it doesn't come, you know, quickly is pseudo progression a phenomenon that's seen in this therapy? No, so not like the checkpoint, not regular checkpoints. Very interesting. Um Doctor Christian Murphy, what do you know about uh late effects after immune therapy such as these? Is there something that the patients should be warned about to, to monitor long term after till therapy or other novel immune therapies? Um Most of the side effects that we see are more acute, you see them right after treatment. Um in terms of long term effects, uh if you're talking a year or two years down the track, there's nothing that um I have come across just yet which uh people need to monitor for. Um obviously beyond a year or two, the risk of side effects are limited. So when we're talking about the, the risks that most of the risks are really early. Ok, Doctor Pak, what have you seen as far as late effects? So basically, these patients will all be exposed to checkpoint inhibitors. So their late toxicity will be uh dictated by the checkpoint inhibitors. And we know with checkpoint inhibitors, you know, long term, uh people can have things like arthritis, arthritis, um uh cardiovascular effects, you know, increased risk of cardiovascular disease. Uh So that would not be really affected by the pills that will actually be dictated by their checkpoint treatment because they all had a checkpoint treatment that didn't go away. Um I'm curious to see if you've had a shared experience with me. Uh in my former institution, I was able to take care of a number of patients on the earlier clinical trials. And a couple of my patients had a complete remission that lasted many years and they continue in complete remission despite having progressed after every other standard therapy for Melanoma. Um interestingly, these individuals basically lost their pigment. Um it started out with vitiligo, right. So patchy pigment loss, but really progressed to total pigment loss. Their hair is white, their eyelashes are white. Have you seen that before? Yeah. You know, we have seen a little I go, you know, for with all the immunotherapies historically, starting with Interferon, you know, high Doyle two checkpoint inhibitors is associated with better outcomes. And there was actually a, a really nice paper from a group at Dartmouth uh a couple of years ago uh showing that uh it's all dictated by the memory t cells with a certain phenotype which are reactive against uh melatonin. Fascinating. It was just really amazing to see. All right. Uh We have no other questions from the audience. I think we'll just conclude briefly by saying, Doctor Christian Murphy, any other thoughts, any last thoughts that you like to leave the audience? Um I'm very excited about the fact that we have this new treatment option for patients with Melanoma and um very excited to see uh more and more patients uh be able to access this therapy. So doctor K. Well, I would urge our uh colleagues, you know, in the community uh to please think about the, the treatment early and uh and even start the preparation work or when the patient is starting the front line checkpoint inhibitor combination therapy or checkpoint inhibitor therapy. Because once they progress, especially if it's uh a primary, you know, progression, uh they may progress rapidly in everyday town. So uh uh a preparation time, uh we'll be happy to uh you be contacted, you know, you can call um our private cell phones. We have a referral numbers, we have emails. Uh We'll be happy to discuss uh in preparation and if the patient uh needs us, we will be then ready and um you know, be able to uh you know, get the treatment to the patient uh quicker. Wonderful. Well, thank you both so much. Thank you to the audience for joining and we will have this available on our website so that people can view after the fact and again. Thank you. It's a really exciting time in our field. Thank you very much. Bye bye.
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