Good day, and welcome to the LAVA Therapeutics Clinical Update call. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your touchtone phone. To withdraw your question, please press star then two. Please note this event is being recorded. I would now like to turn the conference over to your first speaker today, Steve Hurly. Please go ahead. Welcome, everyone, and thank you for joining us at LAVA Therapeutics Clinical Update Call to discuss LAVA-051, our lead Gamma body clinical program. We will be focusing on our initial phase 1/2a dose escalation data from the first 4 cohorts in patients with chronic lymphocytic leukemia and multiple myeloma, which were presented at poster presentations at ASCO and EHA. The two posters summarizing the data can be accessed on our website, lavatherapeutics.com, under the header Scientific Approach. We'll be making forward-looking statements today. Please refer to our current filings with the SEC to review our risk factors. On today's call, I am joined by Dr. Hans van der Vliet, LAVA's Chief Scientific Officer, and Benjamin Winograd, our Chief Medical Officer. We're also very fortunate to have Dr. Arnon Kater, Chairman of the Dutch-Belgian HOVON CLL Working Group, and Professor of Translational Hematology at Amsterdam University Medical Center on this call. Dr. Kater is a LAVA-051 clinical trial investigator and lead author of the ASCO and EHA abstracts. We are encouraged by the favorable safety profile that we have seen so far and potential signs of anti-tumor activity occurring this early during the dose escalation and look forward to providing an in-depth review of the clinical data. Dr. van der Vliet will first provide an overview of LAVA-051's mechanism of action. Then Dr. Winograd will discuss phase 1/2a trial design and summary. Dr. Kater will share his perspective on the data that were presented at ASCO and EHA. I will then highlight the additional clinical milestones for LAVA-051 that we anticipate through the first half of 2023. Following, we'll open it up for your questions to LAVA team and Dr. Kater. Let me turn it over now to Hans. Hans? Thanks, Steve. At LAVA, we would develop two bispecific gamma9 delta2- T cell engaging formats that potentially translate to a favorable therapeutic window. With respect to efficacy, our engagers typically have high potency with EC50s in the low picomolar range. We do not co-activate immunosuppressive regulatory T cells that are known to dampen antitumor efficacy of cytotoxic T cells and are triggered by conventional CD3 T cell engagers. Our engagers can orchestrate innate and adaptive immune responses, potentially resulting in potent and durable responses. Gamma9 delta2- T cells show activity against hematologic malignancies and solid tumors, including immunologically cold tumors. There's also the potential for expansion of gamma9 delta2- T cells, and this can result in an increased number of antitumor gamma9 delta2- T cells. With respect to safety, we think our conditional activation has high precision, and there's a greatly reduced potential for cytokine release syndrome, and we have seen no evidence of CRS in non-human primate studies. The two bispecific T gamma delta T cell engaging formats that we develop are shown in the left corner. One is a bispecific VHH single domain antibody, and the other is a bispecific VHH with an Fc domain connected. Both are small molecules. The bispecific VHH format is used in the lead hematological program, LAVA-051. The other format is used for the lead solid tumor program, LAVA-1207. Next slide. LAVA-051 targets cluster of differentiation 1d, CD1d, which is an MHC class I related glycoprotein best known for its ability to present lipids and glycolipid antigens to natural killer T cells. CD1d is expressed on the surface of various human antigen-presenting cells, including dendritic cells and B cells, but also expressed by various malignant tumors, including several hematologic malignancies such as CLL, AML, T-ALL, and multiple myeloma. Several solid tumors are known to express CD1d. CD1d is also expressed by immunosuppressive cells in the tumor microenvironment, such as myeloid-derived suppressor cells and tumor-associated macrophages. CD1d iNKT cell axis-directed therapies that have been explored in the past using glycolipid antigens and NKT adoptive cell therapy studies demonstrated a favorable toxicity profile. Next slide. LAVA-051 stimulates both type 1 NKT cells, invariant NKT cells, and gamma9 delta2 T cell effector functions and proliferation. This is illustrated in a simplified manner in the graphic. The bispecific molecule crosslinks CD1d on the tumor and the delta2 T cell receptor chain on gamma9 delta2 T cells, resulting in activation and release of cytolytic molecules. The CD1d binding arm has the unique ability to also stabilize the interaction between CD1d and the type 1 NKT cell receptor. This results in strong activation of NKT cells as well, which can release cytolytic molecules to kill the tumor cell. These four figures on this slide illustrate various aspects. The left top figure shows that cytotoxicity of CD1d-positive T-ALL cells can be induced with this engager and mediated by either type 1 NKT cells or gamma delta T cells. Both type 1 NKT cells and gamma9 delta2 T cells can be triggered to expand during a seven-day co-culture. This is shown in the right top corner. The left bottom corner illustrates that cytokines can be produced by either type 1 NKT cells or gamma9 delta2 T cells. Shown in the right bottom corner, you see a feature that we typically see with our engagers, and that is the preferential activity of the gamma9 delta2 T cells activated by the engager to trigger lysis of tumor cells expressing the target of interest and sparing of normal cells. Here illustrated for CD1d with killing of multiple myeloma cells expressing CD1d, while minimal activity is observed against normal B cells and monocytes that express CD1d. Next slide. CD1d is expressed on tumor cells of patients with CLL, multiple myeloma, and acute myeloid leukemia, as illustrated on this slide. This slide shows individual patient data of expression of CD1d. In acute myeloid leukemia, expression is mostly observed in on the monocytic and myelomonocytic subtypes of disease. Next slide. This slide shows activity of LAVA-051 using patient tumor samples of patients with CLL, MM, and AML. In the left figure, you see that a patient's gamma nine delta two T cells present in patient tumor samples can be activated for degranulation. And the right panel shows that patient tumor cells, CLL, MM, and AML, can be lysed by NKT and gamma delta T cells as a result of LAVA-051 addition. The next slide shows an illustration of the antitumor activity of LAVA-051 in vivo. In the left figure, this is illustrated using a model where CD1d-expressing multiple myeloma cells were infused IV on day 0, and treatment started from day 7, consisted of either the CD1d gamma 9 delta 2- T cell engager alone or mice transferred with type 1 NKT and gamma delta T cells alone or in combination with the engager. Only in the latter combination, the LAVA-051 molecule triggers efficient lysis translating into improved survival in mice. The right figure illustrates that, also when using PBMC, so non-pre-activated, non-pre-expanded gamma 9 delta 2- T and NKT cells, also in this setting, antitumor activity can be triggered. Here, CD1d-expressing T-ALL cells were admixed with PBMC and implanted subcutaneously and treatment, as indicated with the red arrows, was performed biweekly using IP administration of LAVA-051. The red lines illustrate the delay in tumor growth and increased survival as a result of LAVA-051. Next slide. To explore the safety of targeting gamma9 delta2- T cells a bit further, we used non-human primate studies where we explored the activity and safety of a surrogate engager termed LAVA-039 because LAVA-051 does not cross-react with the non-human primate T cell receptor nor CD1d. LAVA-039 is a surrogate molecule that consists of a single chain Fv specific for the Vgamma9 chain and a CD1d-specific single domain antibody, both cross-reactive. This LAVA-039 molecule was explored in a single dose and multiple dose studies as indicated on the slide. In these studies, we saw no clinical signs of toxicity, no clinical chemistry abnormalities, no histopathological abnormalities, no depletion of CD1d positive B cells or monocytes as illustrated also in the figure at the right bottom. Only a low cytokine spike as illustrated in the left bottom series. Importantly, we could detect binding of the engager to gamma delta T cells in circulation after dosing. After dosing, we saw a drop in the gamma delta T cell frequency in circulation with a rapid recovery thereafter, and we could detect signs of activation markers on the gamma delta T cells after dosing, as here illustrated in the right top figure looking at CD69 expression. Next slide. To summarize the mechanism of action of LAVA-051, it is a 27 kilodalton humanized bispecific single domain antibody. It directly engages CD1d and the Vdelta2 TCR chain of gamma9 delta2- T cells to mediate potent killing of CD1d expressing tumor cells. It additionally also results in triggering type 1 NKT cells, as discussed. CD1d is expressed by tumor cells in the majority of patients with CLL, MM, and AML. LAVA-051 has high potency with low potential for cytokine release syndrome, affording an anticipated wide therapeutic window. For the clinical trial design, I'll hand it over to Benjamin. Thank you, Hans. Let me jump right into the design of our phase 1 trial study. Our European dose-finding study is ongoing in three countries where we cleared the CTA, the Netherlands, Spain, and Italy. In the U.S., the IND was cleared just recently, and US sites will be able to participate at this dose-finding study as they clear the local requirements. The phase 1 goal will be to determine a biologically active dose as the recommended phase II dose, and that will be based on preclinical data. As you have heard from the data before, we expect from this class of bispecifics a wider therapeutic window than what is seen today with the CD3 bispecifics. For the phase 2A of this study, we are going into disease-specific expansion cohorts in CLL, multiple myeloma, and AML. We want to explore early clinical activity in those respective patients with high unmet medical need. Next slide. Specifically for the phase 1 study, we choose an accelerated titration schedule in patients with relapsed refractory CLL, multiple myeloma, and AML. We'll add a separate cohort at a point when we have reached an initial pharmacologically active dose. The accelerated titration was basically chosen because we knew that the starting dose is totally based on in vitro data, as you have seen before, and that traditionally is a low starting dose. As you will see in the following, when Dr. Kater presents the data in four stepping stones, we could reach 100 times the starting dose. Specifically, the primary objective of the study is to determine the recommended phase 2 dose. We are looking widely into PK/PD immunogenicity data and obviously preliminary anti-tumor activity, not forgetting the overall safety of the drug. LAVA-051 is administered as two hours infusion, and from the next dose level onwards, we'll also study subcutaneous administration of the same drug. The drug is given on day 1 and day 8, and then after that, twice a week. Let me introduce now, Dr. Arnon Kater, one of our investigators in this study, who will take you through the early clinical data. Thank you, Benjamin. Hello, everyone. I'm Dr. Arnon Kater, and as Steve mentioned, I'm the chairman of the Dutch-Belgian HOVON CLL Working Group. I'm a Professor of Translational Hematology at the Amsterdam University Medical Center, and I am a clinical trial investigator of the LAVA-051 study. I'm also a practicing physician, and I've been treating patients for, let's say, over 15 years. From a research standpoint, my focus is on the biology and treatment of B-cell malignancies, with chronic lymphocytic leukemia as main disease serving as a B-cell malignancy model. There, I specialize in the interaction of tumor cells with microenvironment and specifically with T cells. First, let me tell more about CLL and multiple myeloma treatments and unmet medical needs that still exist for these two diseases. For both chronic lymphocytic leukemia and multiple myeloma, the treatment landscape has evolved considerably over the past decades. For CLL, what treatment approach and sequence is taken depends on the disease stage, the patient's age, and the existence of comorbidities. Targeted therapies have been added to the primarily chemotherapy-based treatments, the BCL-2 inhibitor, venetoclax, and the Bruton tyrosine kinase inhibitors, which are now broadly evaluated at various stages of disease and in different patient segments and combinations. CD20 antibodies also have a major role in the treatment of CLL, with rituximab being the first, yet newer CD20 antibodies, such as obinutuzumab, are now also approved. They are often combined with chemotherapy or one of the other targeted therapies. For multiple myeloma, the treatment approach, sequence, and combination is based on age, fitness, and eligibility for autologous hematopoietic stem cell transplantation of the patients. Next to alkylators, proteasome inhibitors and immunomodulatory drugs have been added to the treatment options. CD38 antibodies have also made a change for multiple myeloma patients, with daratumumab leading the way to the list of treatments available. More recent BCMA-targeting antibody drug conjugates and CAR T cells have been approved for multiple myeloma. Also, bispecific antibodies targeting BCMA have been in clinical trials. Yet, despite these advances, CLL and multiple myeloma remain incurable, and there still exists an unmet need for these patients, and the vast majority will become refractory to or develop resistance to existing therapies. Let's turn to the initial clinical data of LAVA-051 phase 1/2A trial in CLL and multiple myeloma. I will present the latest data as were presented recently at ASCO and EHA. In this phase 1 study, high-risk patients with relapse/refractory multiple myeloma and CLL patients are included. These patients will generally have failed all available standard of care therapies for CLL or multiple myeloma. For CLL, the median of prior treatment regimens was 4. For multiple myeloma, the median of prior treatment regimens was 5. Following the accelerated titration design of the study, we were able to escalate the dose of LAVA zero five one to 100 times of the starting dose. So far, we evaluated cohorts with doses of 0.45, 3, 15, and 45 µgs of LAVA zero five one. CD1d expression was confirmed for all enrolled patients on the tumor cells. So far, 4 out of 7 patients were evaluable during the DLT period. Two, unfortunately, had to come off treatment due to a COVID infection. 1 recently enrolled patient was still in the DLT period. Overall, LAVA zero five one was well-tolerated. Importantly, no cytokine release syndrome, CRS, has occurred. Also, no immune effector cell-associated neurotoxicity syndrome or ICANS was seen. This is important as both CRS and ICANS are frequently occurring at various degrees in patients treated with bispecific T cell engagers and CAR T cell therapies. In addition, no dose-limiting toxicities have been observed. All adverse events equal or higher than grade 2 during Cycle 1 are shown in the table, and the majority of these were not suspected to be related to LAVA-051 treatments. The events that are not suspected to be related are indicated by NS, not suspected, and those that are suspected to be related to the drug are indicated by S, suspected. The grade 2 fever reported for a CLL patient receiving 50 micrograms of LAVA-051 occurred in conjunction with initiation of a tumor flare reaction approximately 1 week after first dosing. I will come back to this tumor flare later in the presentation. A neutropenia grade 3 was reported for a multiple myeloma patient receiving 45 micrograms of LAVA-051 14 days following first treatments. This readily resolved after 1 dose of filgrastim. An infusion-related reaction, grade 2, was reported to occur within 15 minutes of end of the infusion. This did not reappear during following infusions, for which clemastine and paracetamol were administered at prophylaxis. Until now, we see a very benign safety profile of the drug. Pharmacokinetics of LAVA-051 was linear, consistent, and predictable. The graph on the left shows the dose versus the area under the curve or AUC. The area under the curve reflects the actual body exposure to, in this case, LAVA-051 after administration. You can see that most of the data points are on a straight line, which means that there is a linear correlation between the dose of LAVA-051 and the body exposure. There is one data point not on a straight line. As for this patient, several samples for PK measurements could not be collected, and thus the area under the curve calculation was unreliable. The graph on the right shows the consistency of the measured LAVA-051 peak concentrations after dosing in the blood of patients in cohort 4. This is the 45 microgram cohort. Hence, there is thus far no indication for the development of anti-drug antibodies. Pharmacodynamic parameters that we investigated included the measurement of Vgamma9 Vdelta2- T cell frequency, as well as the activation status. The Vgamma9 Vdelta2- T cell frequency in the blood was measured at baseline and was followed after dosing. We typically observed early drop in the frequency of the Vgamma9 Vdelta2- T cells in peripheral blood, followed by a rapid recovery to approximate baseline levels. In the next slide, I will explain more about the dynamics of the Vgamma9 Vdelta2- T cell frequency. The activation markers CD25 and CD69 were used to investigate the activation status of the gamma delta T cells. In all patients where these assessments could be done, we observed an increase in expression of either the activation marker CD25 and/or CD69 after dosing. In one patient, we could reliably assess the type 1 NKT cell compartment and observed a similar increase in the activation markers. We also measured the amount of LAVA-051 bound to the gamma delta T cells, which we call receptor occupancy. You can see that with increasing dose, the receptor occupancy goes up. The outlier of the third patient dosed at 45 micrograms can be explained that for this patient, we could not collect samples early after dosing. In this case, the receptor occupancy was only determined after 72 hours. In accordance with the absence of clinical signs of CRS, we observed no relevant changes in levels of the CRS-related cytokine IL-6 in the peripheral blood of patients after dosing. This slide further illustrates the PD findings and shows that these PD measurements reflect the mechanism of action of LAVA-051. The left graph shows that gamma delta T cell frequency in peripheral blood shows an early drop and subsequent recovery after administration of LAVA-051. The same pattern was noted in the non-human primate studies that Hans presented and may be related to early redistribution after activation. In the middle graph, you can see that after LAVA-051 administration, gamma delta T cells were indeed activated, as shown by the consistent observation of an increase in the expression of activation markers CD25. We have similar data for the activation marker CD69 as indicated on the previous slides. The right graph shows that gamma delta T cell receptor occupancy of LAVA-051. You can see that the peak of receptor occupancy increased dose dependently. Now, what is really encouraging is that potential signs of activity of LAVA-051 were already seen. First in a CLL patient that I treated myself. She was treated with 15 microgram of LAVA zero five one. During the first cycle of treatment, she developed a temporary enlargement and tenderness of several CLL involved lymph node stations. The photo provides an example of one of these temporarily enlarged lymph nodes in this patient. This enlargement was accompanied by fever, and as we ruled out other potential causes for enlargement of the affected lymph nodes, we concluded that these observations best fitted with a tumor flare reaction. Interestingly, this picture was reminiscent of tumor flare reactions that I've previously observed in CLL patients treated with lenalidomide and IMiDs, where it was reported to be associated with response to therapy. The enlarged lymph nodes in this patient subsequently regressed, and the patient had radiologically confirmed stable disease at the 12-week imaging assessment. In addition, there was a notable drop in the percentages of clonal B cells in these patients from 42% of those lymphocytes at baseline to 9% at the assessment at the start of Cycle 4. The second potential sign of activity was found in a multiple myeloma patient who was heavily pretreated and refractory to prior lines of treatment. In this patient, we observed an interesting 23% reduction in M protein levels produced by the myeloma cells. Unfortunately, both patients came off treatment due to COVID. In conclusion, we now presented the first clinical data of a novel class of therapy, bispecific gamma-delta T cell engagers. Far, LAVA-051 was overall well-tolerated. What is indeed noteworthy is that we have seen no CRS, no ICANS, and no dose-limiting toxicities until now. The pharmacokinetics was predictable and linear, and no anti-drug antibodies were determined. Furthermore, pharmacodynamic assessments were in line with the mechanism of action, showing early signs of engagement of gamma delta T cells. Even the first potential signs of clinical activity were noted in a CLL and a myeloma patient. This trial will continue and will now also include sites in the U.S. as the IND was cleared. This trial will also evaluate subcutaneous dosing. With that, I'll hand back to Steve Hurly. Thank you, Dr. Kater, for your informative presentation and for participating in our LAVA-051 clinical trial. We are making early advances with LAVA-051, and we are pleased to see a favorable safety profile, early encouraging signs of potential antitumor activity, and a desirable pharmacokinetic and pharmacodynamic profile in patients with lymphocytic leukemia and multiple myeloma. We will continue to enroll patients in additional cohorts in Europe and the U.S. as we look to identify the recommended phase 2 dose. Looking ahead, we expect phase 1 data readout in the second half of 2022 and initial phase 2a expansion cohort data in the first half of 2023. Now we'd be happy to take your questions. Operator? We will now begin the question-and-answer session. To ask a question, you may press star then one on your touch tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. The first question comes from Chris Howerton with Jefferies. Please go ahead. Hi. Good morning. Thank you very much for the presentation and for taking the questions. I guess there's just maybe three from me. First and foremost, you know, obviously, I think it's great that dose escalation by virtue of the work in Europe. Can you remind us of what is the expected therapeutic range or efficacious doses that we should be looking forward moving forward? Question two would be, you know, a little bit of a difficult these are end of the road patients, but what would the expected kind of progression-free survival be in these multiple myeloma or CLL patients? How is, you know, obviously, I think I appreciate your perspective on the observation of. Has it changed in any way you're observing the patients or conducting the study or looking out for these types of adverse events moving forward? Thank you. Hey, Chris. Thanks for the question. Much appreciate your time on the call today. Benjamin, do you wanna take a first shot? Yeah. Your first question was around what is the expected active dose. I mean, clearly. Yeah. As mentioned, we had to start based on in vitro data, supposedly a relatively low starting dose by experience. We have worked quickly upwards to the factor 100, I think we have said before, and based on preclinical data, we start moving now into the more relevant dose levels. As we said, the recommended Phase II dose is going to be driven by optimal biological observations. Traditionally, in order to find that plateau, we will likely have to go up and potentially, again, go a step down because a higher dose is not needed. I think we are moving into that direction where we are seeing more relevant dose levels. With respect to your second question, which is the expected time for progression. I mean, these patients are progressing as they come into the study. Maybe, Arnon, you can say a little bit more to what is expected for these patients if they don't go on the study. Yeah. Thank you, Benjamin. For CLL, then you have to look at the different cohorts, right? You have Richter's transformation, which is just much more aggressive, transformed way of CLL. That life expectancy is very short, 3-6 months, specifically if patients do not respond to chemoimmunotherapy, which almost by definition would be the case in this study since it's a phase 1 study, so no other options should be available. For CLL, it's a bit more blurry, I have to say, because there are not that many patients yet that are double refractory. Double refractory in CLL means both to venetoclax, the BCL-2 inhibitor, and ibrutinib, the BTK inhibitor, or acalabrutinib or the different BTK inhibitors that you have now. There's one paper from, I think it was from MD Anderson half a year ago, and that showed that double refractory patients have also a life expectancy of something like six months. I think that's a bit where you're looking at, if you do really look to this, end of the road, phase 1 trial. I guess the last question that I had was just kind of, you know, the observation of the tumor flare. Did that change your trial conduct or anything that you're looking out for specifically as it relates to that? Can you repeat the question, sorry? Yeah. The question was around the observation of the patient that was dosed at 0.15 micrograms, I believe. There was an observation of the tumor flare. I'm asking, is that something that you're looking out for moving forward as the study progresses? Or how should we be thinking about that event? That's a good question. The whole tumor flare is actually very well known in CLL, based on early data on lenalidomide. Before we had all the specific inhibitors, the BTK inhibitors and venetoclax, a lot of people, including ourselves, tried to combine chemotherapy with lenalidomide, which works as this immunomodulatory drug, which is very active, you know, in myeloma. What was seen was that with much lower dose, you actually had very good activity there, possibly due to T cell activation. There was a good correlation between the occurrence of a tumor flare reaction and responses later on. Of course, we still need to wait with gamma delta T cells if you can expect the same thing. The fact that you got this local inflammation in a lymph node which was tender and painful and later on, reduced in size, I think it was a positive sign. Of course, we have to monitor very carefully if this is something we see in all patients happening. Important, a tumor flare reaction can also be cumbersome. It can almost give like a cytokine release syndrome, but in this patient, it was mostly a localized tumor flare without too much systemic symptoms. Does that address your question? Yes, it does. Maybe- Thank you. Maybe just to clarify, this is very specific for, or specifically, has been observed in CLL patients and not. Yeah. in multiple myeloma Very good. Thank you. The next question comes from Daina Graybosch with SVB Securities. Please go ahead. Hi. Thank you all for the time and for taking questions. I have a couple around dose. I'm wondering, you know, what receptor occupancy on the gamma delta T cells you're aiming for based on the preclinical. The second question is whether you looked at receptor occupancy on the tumor cells that are expressing CD1d. The third is, how are you thinking about optimizing, not dose but dose frequency? It looks from this data, and correct me if I'm wrong, they're getting a pretty quick spike in receptor occupancy and then clearance. Do you think that you may need to dose more frequently? Thanks for the question, much appreciated. Hans, would you like to talk to receptor occupancy? Yeah, sure. The receptor occupancy that is required to trigger gamma-9 delta-2 T cell activation in vitro is fairly low. We see activation of these cells from approximately 1% and higher. The question what receptor occupancy level we are aiming at is in that sense a bit difficult to answer because it's not a. It is a dynamic measurement. The levels that we have reported are the peak levels after dosing. Clearly we would if the safety profile permits we would like to move up to to potentially full saturation and also observe more prolonged receptor occupancy levels over time. We have also looked at, and we measure, receptor occupancy on the tumor cell as well. The difficulty there is that the level of CD1d expression is less pronounced than it is for the T cell receptor expression on a gamma9 delta2 T cell. It is more difficult to reliably assess the binding. At this time, we cannot safely say that we can actually measure compound binding on the tumor cell compartment yet. This is something that we continue to monitor across the trial. The question on the dosing frequency. We started with twice a week dosing, IV, based on in vitro work that we have done. We also have non-human primate data with a surrogate engager. We expect to have the bispecific present on the surface of the gamma delta T cells for a prolonged period of time, so approximately four to five days in vitro and in the non-human primate studies. We are measuring the receptor occupancy over time, and hopefully that will also guide us or inform us on whether we can reduce the dosing frequency. In mouse studies that we have been performing, we have also looked at more extended dosing intervals, and we also see antitumor activity, for example, when we reduce the dosing frequency to once weekly or even once every two weeks. It is unlikely at present, we believe, that we would need to increase the dosing frequency. It would be more likely that we stick to this or can reuse it in the future. That's very helpful. Thank you. The next question comes from Jessica Fye with JP Morgan. Please go ahead. Hey, guys. Good morning. Thanks for taking my questions. Can you clarify a little more specifically how you're gonna introduce subq dosing into the trial? And can you also tell us about the patients who came off of study due to COVID? Have you tracked them and how they've done? Yes, thanks for participating. Benjamin, you want to talk to subcu? Sure. Based on the fact that we, as Hans showed, we have difficulties with the original compound to conduct any medium count studies in animals based on the non-cross sensitivity, we will at the next dose level look at patient-by-patient bioavailability by giving the patient one subq dose and one IV dose or the other way around. It will help to understand what is the order of magnitude of bioavailability, and we will adjust subcu dosing for subcu cohorts subsequently. Regarding to remind me what your second question was. The patients, who you note on the poster came off the study due to COVID. Did you track how they did over time? Yeah. Both of the COVID patients, unfortunately, passed away. Got it. Thank you. If I can add to that's something we unfortunately have seen, specifically in CLL patients. It's also reported in literature that if patients with CLL, which have both T cell dysfunction perhaps, but also a very large B-cell and humoral immune problem, well, the chances of a very high risk COVID and death as a consequence, specifically when there are so many lines of treatment, that's really a signal that we see. Thank you. The next question comes from Sebastiaan van der Schoot with Kempen. Please go ahead. Hi, team. Good afternoon, and thanks for taking my questions. The first one is on the difference between the Vδ1 and Vδ2 populations. We saw a few gamma delta therapeutic modalities presented at ASCO, and I was wondering if you could remind us of the difference between those specific subpopulations and why you or what the advantages are of the Vδ2 population. LAVA-051 also activates NKT cells. Are you tracking any activational markers from those type of cells? The last question is for Dr. Kater. In your experience, have you ever treated with T cell engagers or CAR T? Can you maybe elaborate on what your views are to what extent CRS and ICANS is still challenge in the clinical setting? Sebastian, thanks for joining the call. Hans, would you like to start with Vdelta 1 versus Vdelta 2? Yeah, sure. Sebastiaan, indeed, there's two dominant populations of gamma delta T cells, the delta twos and the delta ones. The delta two cell population is the more abundant population in peripheral blood. About 90% of all gamma delta T cells is a gamma nine delta two T cell, and it is also a very homogeneous population. They have a monomorphic T cell receptor. They interact with a restricted set of antigens, phosphoantigens, and they have a homogeneous phenotype, which is a pro-inflammatory cytotoxic phenotype. These cells are known to or can infiltrate many different tumors, and in cancer, they are positively associated with favorable outcome. The delta one population is a much more diverse population, so the delta one chain can pair with different gamma chains. Related to that, it is also diversity with respect to antigen specificity and related functional diversity. The delta one compartment consists of cytotoxic T cells, but it also consists of cells that have a pro-tumor or regulatory phenotype. It is much more diverse. In the setting of cancer, there's a variable association between delta one frequencies and outcome. As an illustration, there's also a company that actually has as its focus the depletion of the delta one compartment, to relieve immune suppression in this tumor microenvironment. For the delta ones, companies that they are mostly working on adoptive cell therapy approaches with a CAR introduced for targeting, the delta two population that we target is, as I said, more, has a more consistent phenotype, is more abundant. We think the total numbers of this cell population are in the range of numbers that have been given for successful CAR T cell therapy. With an off-the-shelf bispecific antibody approach, we think that is a more straightforward approach to employ gamma delta T cells. With respect to the question on NKT cells, that's indeed another mechanism of action of LAVA-051. In the trial, in addition to the gamma9 delta2- T cell frequency and activation status throughout treatment, we also monitor NKT cell frequencies at baseline and throughout treatment, and also the activation status of these cells. Typically, the NKT cell compartment is smaller in size, so it's also more difficult sometimes with these low numbers to reliably assess any markers on these cells. But in one case in the trial thus far, we've been able to measure reliably the activation status on NKT cells and also those data pointed towards activation of NKT cells after dosing with LAVA-051. Was there a follow-up? Yeah, I think it was also a question for me about CRS. Yeah. What was the exact question? The question was whether in your experience that with the use of T cell engagers or CAR T, that CRS and ICANS is still problematic in the clinic. Yeah. It for sure is. We recently have reviewed data on the phase 2 study for one of the CAR-T companies for mantle cell lymphoma. There you really see high levels of high-grade CRS, which is a problem for those patients for sure. For bispecific antibodies in the space of CLL, there is only very scarce data. You have the LAVA study as far as we know, and you have the epcoritamab, which is CD3, CD20, the normal alpha beta CD3. But that's really, really early with dose expansion data. For the other areas where bispecifics are more used, myeloma and lymphomas, yeah, you have this problem of CRS. Of course, with the fact that we can now use IL-6 inhibition, Tocilizumab, that of course helps a lot, but it's still a risky procedure because of that. Maybe I'm not sure if that answers your question, but I think we now much better know what it is and how to treat it, but it's still a clinical problem. Okay, great. Thank you. That was really clear. This concludes our question and answer session. I would like to turn the conference back over to Steve Hurly for any closing remarks. Thank you. Thank you, everybody, for attending and very insightful questions. We are excited so far with the data we've seen, and we look forward to continuing enrolling these trials in Europe and the U.S. and sharing more data later this year. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.