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Jun 2, 2020

In today's episode, we hear from Dr. Raghuveer Ranganathan, a clinical instructor in the Division of Hematology and Oncology at the UNC School of Medicine at Chapel Hill. His clinical focus is lymphomas and leukemias, with a specific focus on using cellular immunotherapy to treat patients with hematologic malignancies. Dr. Ranganathan discusses how the treatment landscape has changed with the introduction of CAR-T therapies and other advances in cellular immunotherapy techniques.



ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carol, a reporter for the ASCO Daily News. Today I'm speaking with Dr. Raghuveer Ranganathan, a clinical instructor in the Division of Hematology and Oncology at the University of North Carolina's School of Medicine at Chapel Hill. His clinical focus is lymphomas and leukemias, with a specific emphasis in using cellular immunotherapy to treat patients with hematologic malignancies.


His research on cellular immunotherapy techniques, such as optimized TCR and CAR T-cells, has been published in peer-reviewed journals, and his work has been recognized by the Lymphoma Research Foundation and the American Society of Hematology. Dr. Ranganathan reports no conflicts of interest relevant to this podcast, and full disclosures relating to all Daily News podcasts can be found on our episode pages. Dr. Ranganathan, welcome to the podcast.


Dr. Raghuveer Ranganathan: Hi, Geraldine. Thank you for inviting me and having me on your podcast today.


ASCO Daily News: Dr. Ranganathan, how has the treatment landscape changed with the introduction of CAR T- cell therapies for hematologic diseases?

Dr. Raghuveer Ranganathan: The CAR-T therapies have really revolutionized our treatment options in general. Currently, the main pillar of front-line treatment for hematologic malignancies is chemotherapy, with radiation sometimes playing a supportive role, and surgery being a rare adjunct. Now immunotherapy, and specifically cellular immunotherapy, has formed an additional and critical option for these diseases, especially in the relapsed refractory setting.


In particular, CAR T-cell therapy has provided hope in achieving long-term remissions, and maybe even a cure in patients, with these hematological cancers who are chemorefractory, or have exhausted all other treatment modalities due to the persistence of their disease. Interestingly, due to the success in multiple-relapse refractory disease, CAR T-cell therapy is being explored as an option earlier to patients with relapsed refractory disease.


As stated, chemotherapy is still the front-line option for hemotological malignancies. As an example, for diffuse large B-cell lymphoma that is not a double- or triple-hit variant, the standard of care is still R-CHOP as front-line therapy. And if the patient relapses systemically, then the goal is to give salvage chemotherapy, with the hope of proceeding to an autologous stem cell transplant, if they're in CR and transplant-eligible.


CAR-T is approved for a second relapsed disease and beyond in lymphomas. It's thought, though, that patients who have been exposed to high-dose chemotherapy or numerous salvage chemo regimens display less P-cell fitness overall, which subsequently reduces the cytotoxic efficacy of CAR T-cells derived from those patients' regular T-cells. As a result, there are ongoing clinical trials comparing the use of CD19 targeting CAR T-cell therapy with aggressive B-cell lymphoma in first relapsed, and comparing it prospectively against autologous hematopoietic stem cell transplants.


ASCO Daily News: So what are some of the recent FDA drug approvals for CAR T-cell therapy that you are now using when treating lymphoma patients, and what you expect to see approved in 2020?


Dr. Raghuveer Ranganathan: So there are two currently FDA-approved CAR-T products that are now available for commercial use. Both CAR-T products target a CD19 antigen present on B-cell derived hemotological malignancies. One of them is axicabtagene ciloleucel, otherwise known as Axi-Cel, or its trade name of YESCARTA. And it's FDA-approved for use in adult patients who have received two or more lines of therapy for relapsed refractory aggressive B-cell lymphomas, which includes diffuse large B-cell, including high-grade variants, primary mediastinal B-cell, and transform follicular lymphomas.


The other CAR-T product is also CD19-targeting, named tisagenlecleucel, which we will call as Tisa-Cel, its trade name being KYMRIAH. And it has two indications as part of its approval. One is for adults with relapsed refractory diffuse large B-cell lymphoma, including high-grade variants and transport and follicular lymphomas. So in other words, the indication's very similar to Axi-Cel, except with the exclusion of primary mediastinal B-cell lymphoma.


The second indication for Tisa-Cel is for use in children and young adults up to the age of 25 years with B-cell acute lymphoblastic leukemia, or B-cell ALL, that is either refractory to treatment or has relapsed twice or more. The main difference between the two CD19 CAR constructs molecularly is that Axi-Cel has a CD28 intracellular costimulatory domain, while Tisa-Cel uses a 4-1BB costimulatory domain. Axi-Cel had an initial overall response rate and a complete response rate of 82% and 58% respectively, with ongoing complete response rates of about 35% at six months in its ZUMA-1 phase 2 trial.


Tisa-Cel displayed an initial overall and complete response of 53% and 40%, respectively, with ongoing Complete Response, or CR rate, at six months of 30% in its Juliet phase 2 trial in its patients. In both trials, those patients who reached and remained in CR at eight to 10 months displayed a high chance of remaining in complete remission long-term. Several patients in both trials demonstrated conversion of a partial response to a complete response as much as 15 to 18 months after Cartesian infusion, though most of these conversions happened within the first six months.


It's difficult to compare the clinical trials for each of these CD19 CAR-T products with each other because each of the trials were conducted in critically different ways regarding patient selection, disease types, allowing bridging therapy or not, and different dosages of lymphodepletive chemotherapy. How these differences matter clinically is yet unknown and requires more research at this time. However, there were some interesting similarities and results between the two trials.


Patients both below age 65 and above 65 did equally well. Germinal center and non-germinal center lymphomas both responded equally to both CD19 CAR-T products. Both trials include a small number of patients with CD19 negative lymphomas, and some of them responded to CAR-T therapy. Also interestingly, the early use of tocilizumab, which is an aisle 6 receptor-blocking antibody used in cases of Cytokine Release Syndrome, or CRS, did not negatively impact response outcomes, and neither did the early use of corticosteroids for CRS and/or neurotoxicity.


Now, in addition to the Axi-Cel and Tisa-Cel, a third CD19-targeting CAR-T product, lisocabtagene maraleucel, or Liso-Cel cell for short, is supposedly nearing FDA approval for 2020 in relapsed refractory lymphoma. Its distinct feature, compared to the other two products, is that Liso-Cel is formulated as specified CD4, CD8 composition ratio administered at a flat dose. At the recent ASH meeting in December 2019 in Orlando, Liso-Cel showed promising response rates that were comparable to Axi-Cel and tisagenlecleucel in relatively short follow-up time. And the pure publication of the data from its clinical trials is still eagerly awaited.


ASCO Daily News: Right. And what about the use of CAR-T therapy in mantle cell lymphoma?


Dr. Raghuveer Ranganathan: So relapsed mantle cell lymphomas, especially with blastoid or pleomorphic morphologies, have a dismal prognosis with available salvage therapies. And this is where CAR-T can hopefully help. At the recent ASH meeting, the ZUMA-2 clinical trial with Axi-Cel in mantle cell lymphoma showed very promising response rates. An overall response rate of 93%, with 67% CR rate, was seen in 68 patients, with most of these patients having relapsed after autologous hematopoietic cell transplants. And the majority showing refractory disease to BTK inhibition, which is the standard therapy after a first relapse.


The CAR-T therapy results appeared to be agnostic towards the morphology of patients' mantle cell lymphoma. Meaning those with the more aggressive blastoid or premorphic variant morphologies responded as well as those with the classical morphologies. Grade 3 or higher CRS neurotoxicity were seen in 15% and 31% of patients, respectively. And we're waiting for the official publication of these results as well to gauge its full efficacy and safety profile in this disease sub-type for lymphoma.


ASCO Daily News: Let's focus on patients with multiple myeloma for a moment. How does CAR T-cell therapy differ for patients with multiple myeloma?


Dr. Raghuveer Ranganathan: So multiple myeloma tumor cells rarely express CD19. So CD19 is not really regarded as a dependable target for myeloma. B-cell Maturation Antigen, or BCMA for short, is a trans-membrane protein which is expressed on multiple myeloma cells. There have been a handful of phase 1 trials looking at BCMA-targeting CAR T-cells in multiple myeloma.


And the first phase I trial was out of the NCI published in 2015, looking at 12 patients who received anti-BCMA CAR at varying dose levels where they had one stringent CR and two very good partial responses, and one partial response, with response durations lasting between 16 and 30 weeks. But eventually all of the patients relapsed, unfortunately. A follow-up trial by the same group using a different anti-BCMA CAR, with a 4-1BB post-stimulatory domain, instead of the CD28 domain used in the first trial, was used in the multi-center phase I trial with 33 patients enrolled.


Similar to their first trial, the new trial had varying dose levels of the anti-BCMA CAR cells as well, and had slightly higher doses given than seen in CD19 CAR trials. An overall response rate of 85% was seen, with 45% CR or stringent CR. Very good partial response and better were only seen in the higher dose levels of at least 150 million CAR-positive T-cells or higher.


Four of these patients showed ongoing CR or stringent CR of 12-plus months at the time of study publication. In a subset analysis of patients whose myeloma tumor expression of BCMA was less than 50%, and comparing them to patients whose BCMA expression was greater than 50%, there was no difference in response. 16 out of 18 patients who were assessed for MRD negativity were negative at 10 to the minus 4 nucleated cells, and median progression-free survival was 11.8 months.


Another phase 1 trial out of University of Pennsylvania, using a fully-humanized anti-BCMA CAR, was administered to 25 patients, either with or without lymphodepletive conditions prior to CAR-T infusion. In the cohort of 11 patients receiving both lymphodepletion and a higher CAR-T infusion dose, an overall response rate of 64% was seen. Since publication of these studies, unfortunately though, the majority of the study patients have all relapsed with disease.


It is somewhat difficult to pinpoint the reason for this large amount of relapse, but it might have something to do with the nature of the BCMA antigen itself. BCMA is cleaved by an enzyme called gamma secretase and shed off of the surface of myeloma tumor cells normally. High levels of soluble BCMA circulating in the peripheral blood, incidentally, is associated with a poor clinical outcome in general.


While the study showed efficacy in a myeloma tumor whose BCMA expression was less than 50%, there is very likely an expression level below which the CAR T-cells will not be effective in identifying and eliminating a tumor. And since BCMA can be cleaved off the myeloma cell surface, it's basically an escape route for the tumor cells to evade detection from the BCMA-targeting CAR. Interesting data shown at the recent ASH Conference out of the Fred Hutchinson Cancer Center showed the addition of an inhibitor of gamma secretase keeps the BCMA from being cleaved and shed off of the myeloma tumor cell surface, thereby increasing its expression levels and keeping it on the tumor cell surface.


When the gamma secretase inhibitor is combined with anti-BCMA CAR-T cells in patients, it preliminarily showed promising long-standing results in a phase 1 trial with six patients. But further follow-up and additional clinical trials are necessary to validate these findings. Additionally, here at UNC Chapel Hill, we have a clinical trial open that uses CAR T-cells targeting CD138, which is another antigen also expressed on myeloma cells instead of BCMA. We're currently enrolling patients and hope to see an efficacy in myeloma, which would help advance the treatment paradigm from our studies as well.


ASCO Daily News: Excellent. Well, Dr. Ranganathan, I think it's important to address the issue of toxicities. So how are the toxicities unique to CAR-T being addressed? And do you foresee a time when biomarkers will be used to predict toxicity in patients?


Dr. Raghuveer Ranganathan: Sure. The two toxicities uniquely seen with CAR-T therapy are Cytokine Release Syndrome and Neurotoxicity, otherwise known as ICANS. The pathophysiology of these two toxicities is still somewhat unknown, and an area of concerted investigation currently. Cytokine Release Syndrome, or CRS, is a systemic inflammatory response produced by a superphysiologic elevation of cytokines. IL-6, in particular, seems to be a culprit.


Cytokine analyses have shown a relation between higher peak levels of IL-6 and higher grades of CRS in CAR-T patients. It's characterized by a constellation of symptoms, which include fever, malaise, headaches, myalgias, and arthalgias and rigors with fever usually being the first symptom observed with CRS onset. Though it's time of onset can vary from a few hours to more than weeks post CAR-T infusion.


In severe CRS, patients can have life-threatening hemodynamic instability, stemming from capillary leakage, hypoxia, coagulopathy, and organ dysfunction. Risk factors for severe CRS include high tumor burden, higher intensity of lymphodepletive chemotherapy prior to cell infusion, a higher level of administered CAR-T cell dose, and possibly also elevated inflammatory markers at baseline prior to infusion, such as abnormally high C-reactive protein and ferritin. Since high elevations of IL-6 were noted in the early CD19 CAR-T trial patients, administration of tocilizumab, a monoclonal antibody blocking the IL-6 receptor, was noted to demonstrate a rapid de-escalation of CRS symptoms. So now tocilizumab is actually a mainstay of treatment for CRS.


Corticosteroids are also used in the treatment of CRS, especially if tocilizumab is not enough to curtail the symptoms. As I had already mentioned, earlier intervention with tocilizumab and/or corticosteroids did not appear to negatively impact CAR-T efficacy in clinical trials. Now, the second unique toxicity is neurotoxicity, which is now termed as Immune Cell Associated Neural Toxicity Syndrome, or ICANS for short.


It can manifest as a tremor, impaired attention, difficulty writing, expressive aphasia, and confusion, but also can develop into more serious symptoms such as encephalopathy, delirium, stupor, and seizures. In rare cases, diffuse cerebral edema has developed, sometimes as a progressive crescendo, but occasionally also with very little preceding warning or clinical signs. ICANS can happen during CRS, but more commonly occurs after CRS, and can lag behind CRS by up to two weeks.


Expressive aphasia is the most common characteristic symptom that develops first in patients before other symptoms, with the symptom progression taking anywhere from hours to days. Though cytokines leaking through a disruptive blood brain barrier is theorized as a possible cause of ICANS, its pathophysiology really remains largely unknown, and is a hot area of study currently. Unlike with CRS, treatment with tocilizumab does not lead to symptom benefit because tocilizumab does not cross the blood-brain barrier. So corticosteroids are really the only option for treatment of ICANS at this time.


ASCO Daily News: So what's on the horizon for CAR T-cell therapies? Do you think they will be used to treat solid tumors in the future?


Dr. Raghuveer Ranganathan: So far as the horizon and future directions for CAR T-cell therapies, there are already several modifications and upgrades being attempted to improve the current science and technology. One such enhancement is adding additional co-stimulatory intracellular domains to the actual CAR construct, a so-called "third generation" CAR-T. The idea is that by increasing that matter of costimulatory domains in the CAR construct, such as adding a CD28 costimulatory domain to the 4-1BB costimulatory domain that might be already present, there can perhaps be either amplification of signals within the CAR-T cells, and also harnessing of the different properties inherent to each different costimulatory domain, with augmented proliferation tumor cytotoxicity as a result.


Currently, however, third-generation CAR-T constructs have yet to show better tumor cytotoxicity and better long-term remissions clinically, compared to second-generation constructs. Another enhancement is targeting two antigens simultaneously, or dual-targeting CAR0T. One of the purposes of this approach is to minimize tumor escape.

Since the current second generation CAR T-cells target one cancer antigen at a time, if tumor cells were to down-regulate the expression of the targeted antigen, it would result in the tumor being able to evade recognition by the CAR T-cells. By targeting two antigens simultaneously, it's thought that the risk for tumor escape is lessened. A spinoff of dual-targeting CAR-T utilizes a sort of Boolean logic-gated approach where the CAR T-cells can be recalibrated to activate in an inducable fashion.


In these logic-gated CAR T-cells, sensing of antigen 1 by a synthetic notch receptor within a modified T-cell then induces transcription and subsequent expression of a CAR receptor, which is specific for antigen number 2. Meaning that without binding of the antigen number 1 by our genetically-modified T cell, there is no expression of the CAR receptor binding to antigen number 2, which could help minimize on-target off-tumor toxicity. Another approach is called T-cells Redirected for Universal Cytokine Killing, or termed somewhat tongue-in-cheek as TRUCK T-cells, a playoff of CAR- T cells.

These cells, in addition to direct tumor killing, also produce a pro-inflammatory cytokine, like IL-15 or IL-18, on coming into contact with a tumor, which helps to recruit a second wave of immune cells in a locally-restricted fashion, hopefully, to initiate a secondary attack on cancer cells, and also help enhance its own proliferation, cytotoxicity, and longevity. Now, there are unique obstacles and challenges for CAR-T and solid tumors that make it more difficult when compared to hematologic malignancies. Some of the existing challenges include overcoming the hostile tumor microenvironment, nutrient depletion, hypoxia, and inhibitory checkpoint molecule expression on solid tumors. Now, any one of these impediments would be a strong stumbling block to try and overcome, but when all of these hurdles occur together all at once, it can be very difficult to combat.


In addition, on-target off-tumor toxicity is somewhat of a bigger challenge to overcome in solid tumors. And a likely cause for this is the overlapping antigen expression on epithelial tissues from which most solid tumor types originate. And also the spatial proximity and restriction of critical sites when targeting solid tumors.

For example, a few years ago, a patient with metastatic colon cancer who had received CAR T-cell therapy as part of a trial died from acute respiratory distressive failure, with the cause thought to be low-levels of being expressed on lung epithelial cells. That said, I do believe CAR T can become a viable treatment modality in solid tumors with some modifications and improvements. One such method being tested in clinical trials is combining immune checkpoint therapy, such as PD-1 inhibitors, with CAR T-cells.

Another possibility is to edit the native inhibitory receptor in CAR T-cells by switching out the inhibitory receptor's intracellular domain for an intercellular domain from a stimulatory receptor. For instance, we take the native PD-1 molecule from a CAR-T cell and edit or switch out the intracellular domain, and put in the intercellular domain from CD28. What you get now is a molecule which has the PD-1 receptor on the outside, but a CD28-signaling mechanism on the inside, so that the net result is actually positive for the CAR-T, which now gets added stimulus instead of inhibition.


Such switch receptors are being incorporated into CAR T-cells to augment their activity and proliferation potential. And as I mentioned before, TRUCK T-cells and logic-based CAR T-cells are also other possible methods to conquering some of these obstacles posed by solid tumors. So while there's still much more investigation to be done in overcoming solid tumors, I do hope that we can make some strong headway in the near future.

ASCO Daily News: Well, thank you Dr. Ranganathan for sharing your insights on CAR T-cell therapies with us today.

Dr. Raghuveer Ranganathan: My pleasure. Thank you, Geraldine.

ASCO Daily News: And to our listeners, thank you for tuning into the ASCO Daily News Podcast. If you're enjoying the content, please rate and review us on Apple Podcasts.


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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.