Zaia Draws on Decades of Innovation in Infectious Disease for Breakthroughs in Gene Therapy – AJMC.com Managed Markets Network

Interview by Maggie L. Shaw

Known as a gene therapy pioneer, Zaia has spent almost40 years at City of Hope, in Duarte, California. He was first drawnby the promise of studying cytomegalovirus. Over the decades, hisgroundbreaking research has encompassed HIV/AIDS, cellular gene transfer therapy, immunotherapy, bispecific antibodies, andnow hyperimmune globulin for workers on the frontlines of thecoronavirus disease 2019 (COVID-19) pandemic.

Known as a gene therapy pioneer, Zaia has spent almost40 years at City of Hope, in Duarte, California. He was first drawnby the promise of studying cytomegalovirus. Over the decades, hisgroundbreaking research has encompassed HIV/AIDS, cellular gene transfer therapy, immunotherapy, bispecific antibodies, andnow hyperimmune globulin for workers on the frontlines of thecoronavirus disease 2019 (COVID-19) pandemic. Zaia was recentlyawarded $750,000 from the California Institute for RegenerativeMedicine to study the potential use of convalescent plasmain patients with COVID-19, as well as to create the COVID-19 Coordination Program to aid in this effort.1

Zaia spoke at length about the crucial connections betweenbasic research in HIV/AIDS and developments in gene therapy.This interview has been edited slightly for clarity.

EVIDENCE-BASED ONCOLOGY (EBO): We know that HIV does notelicit a protective immune response in the body. Do you think itis possible to overcome nature in this regard, to trick the immunesystem into fighting HIV to the degree that it can overcome it, suchas interrupting the binding of the virus to the CD4 receptor?

ZAIA: So, lets take that question apart. There is an immuneresponse in the body to HIV, but its just not protective. Thequestion is, why isnt it protective? And could you overcome thatdeficiency? So, one aspect to understand is the ability of the virusto continuously mutate.

If youre familiar with RNA replication, it doesnt have highfidelity, meaning that mistakes occur while copying the newstrand of RNA. Whereas DNA replication has high fidelity, meaningthat once you copy it, its virtually word-for-word precise with onlyan occasional mutation. So, whenever the virus makes 10,000 basepair copies, theres 1 mistake. But the virus is actually only 10,000base pairs long in terms of its RNA. So that means theres about 1naturally occurring mistake in every new virus. And since therecould be billions of new viruses made, there will be literally allthese mutations a day, some of which could help the virus survive.Since the barriers that put up against the virus for continuing itsreplication are limited (eg, immune response, antiviral medications),its not that hard to imagine that a mutation could occurthat gets around a specific barrier When this occurs, it is calledantigen escape or drug resistance.

The deeper understanding of this question is, in the immunerecognition of the virus, the T lymphocytes have a receptor forthe virus called the T-cell receptor; its really an antigen receptorthat can see a specific peptide on the surface of the virus or onthe infected cell. So, the T-cell receptor itself is the problem. Itsexerting this selection, but it is not very flexibleits rigid. Its anall-or-none thing. If the virus can mutate its protein slightly, thenthat peptide never fits into the receptor. Its kind of like a lock andkey. So, we need a T-cell receptor thats more resistant to antigenescape. Could you make an artificial receptor, called a chimericantigen receptor (CAR), that would better resist antigen escape?At City of Hope, weve been trying to make a T-cell receptor thatyou [could] paste on to the T cells genetically so they are better atresisting this inability to detect the mutated part of the virus.Is there a part of the virus that is resistant to mutation? Thereprobably is. The key surface protein is called gp120. And someantibodies are very broadly reactive to all viruses, all HIV viruses.So, a broadly neutralizing antibody can detect multiple different gp120s, all of which are slightly differentbut theres somecommon feature thats recognized by the broadly neutralizingantibodies. If you put that on a T cell, as a chimeric antigenreceptor, the T cell might be more resistant to antigen escape bythe mutating virus.

The other possibility is, what if you use the CD4 receptor? Thatsan almost immutable part of the virus biology, because if thevirus didnt bind to the CD4 receptor, it probably wouldnt be HIV.It would be a different virus, a different lentivirus. But there areCAR T-cell receptors that utilize not the antibody to find the virus,but the CD4 receptor itself to find the virus. In other words, if youput CD4 on the surface of a CD8 cell, it would find all the gp120because the CD4 and gp120 would bind to each other. So that isactually another concept that can be utilized, and thats currentlyin clinical trials at the University of Pennsylvania.2

So, in summary, I think the trick would be to utilize a modificationof a T-cell receptor that would avoid the ability of the virus tomutate around the classical T-cell receptor and allow the immunesystem to see the virus and to control it.

EBO: The holy grail of HIV research for nearly 40 years has beento produce a vaccine. The Thai trial (RV144)3 has been the onlytrial thus far to show that a preventive HIV vaccine is possible.What have been the barriers to reproducing these results? Why hasachieving the goal of developing an AIDS vaccine been so elusive?

ZAIA: Those are good questions. I dont think anyone knows [theanswers] for sure. But 2 factors are probably important. Again,you go back to the virus mutation issue. Its continuous, and now[its] in the presence of immune pressure placed on the virus bythe vaccine. Youll get selection for these mutations. So, I guessthe question is, did the vaccine make an immune response to themost immutable parts of the virus? Probably notvirus mutationis not the only answer to why vaccines fail. It seems to be somethingmore basic than that.

For example, do vaccines induce mucosal immunity? We have amucosal immunity to many viruses that come in contact with ourmucous membranes via nose, throat, etc. Well, HIV would be inthe mucous membranes of the genital tract and rectum, [usually].So, are these vaccines really making a mucosal immunity where its needed? Thats a possible explanation for why the vaccinesare not working.

An area that people just dont understand at the present timeis why you can make a vaccine for certain viruses that wouldnormally come through the respiratory tract and not be able tomake a vaccine for others. Its relevant to COVID. Will we be ableto make an immune response to COVID when we know that theinitial entry point is through the nasal passages? Thatll be themillion-dollar question.

EBO:Can you explain what a lentiviral vector is? Why is it that HIVcan be inactivated outside the body to be used as a safe lentiviralgene therapy, but we cant do the same with the virus internally?

ZAIA: A lentivirus has a certain structure and is made of RNA andprotein. And it fulfills the requirements from some taxonomiccommittee that defines what a lentivirus is. Basically,it is a virus that can do 1 thing very usefully: it canreverse the RNA to DNA, and the DNA can then beintegrated into the host DNA, become part of the host. And that integration is due to an enzyme calledintegrase. So, it has an RNA that also encodes for thisintegrase as well as reverse transcriptase; it turns RNA into DNA. That was a famous discovery at onepoint; it won the Nobel Prize. And so thats whatmakes it a lentivirus.

Now, you can inactivate it in the sense of makingit safe. It has only 9 major proteins, and thoseproteins are important in those elements that Ijust mentioned and in leading to its pathogenicity.You can remove them and still have some of theelements that you need. For example, you couldleave the integrase but remove other things, whichmay make the virus able to replicate and lead toAIDS. But now youd have an incomplete virus thatyou can put a gene into, and it can be delivered to the cell, because the virus can still get into the cell.And it can still have an integrase, which can helpyou integrate that message or that gene into the hostcell. But the virus cant replicate. It has all the otherparts of it that are needed, but replication has beenremoved. You basically neuter the virus by removingcritical genes. Its still allowed to be a good virusfor your useit can get it into the cell, deliver itspayloadbut it just cant replicate.

The question is, why cant we inactivate certainof these critical genes that are important forreplication? And, in fact, you canin vitro. You cancertainly put in inhibitors of all the various proteinsof a virus. Some of those are called small inhibitoryRNAs (siRNA), which are known to block specificallydifferent proteins of a virus and almost any virus.The question is, how do you deliver that siRNA to allcells that are infected? If you have trillions of cellsinfected, how would you get to the last one? Thatsthe issue. So, you can do it in a test tube, but you justcant do it in a human organism.

Now, you might ask, why are you able to getcertain things to work for acute lymphoblasticleukemia but not for HIV?

Well, I think its because the virus can becomelatent and invisible to most systems and theleukemia cannot. The leukemia is robustly growingand expressing all of its proteins and enzymes,and so we [can fight it with] chemicals and otherthings like CAR T cells, and they will destroy thosecells. The HIV is holed up in an inactive form, aso-called reservoir, and that reservoir is the problem.Once its in there, its like a snake in its hole. Youcannot get to it.

EBO: In a 2016 commentary,4 you discuss thefindings by Yang et al that the immune-mobilizingmonoclonal T-cell receptor, or ImmTAV, couldbe an effective new agent against HIV/AIDS dueto its bispecific antibodybindingproperties. It was shown to haveactivity against both p17-expressingactivated and resting CD4 cells. Is theagent proposed by Yang possible andwithout neurotoxicity?

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Zaia Draws on Decades of Innovation in Infectious Disease for Breakthroughs in Gene Therapy - AJMC.com Managed Markets Network

Mayo Clinic Study of Humanigen’s Lenzilumab Shows Rapid Recovery and Discharge in Severe and Critical COVID-19 Patients – Business Wire

BURLINGAME, Calif.--(BUSINESS WIRE)--Humanigen, Inc., (HGEN) (Humanigen), a clinical stage biopharmaceutical company focused on preventing and treating cytokine storm with lenzilumab, the companys proprietary Humaneered anti-human granulocyte macrophage-colony stimulating factor (GM-CSF) monoclonal antibody, announced data on the first clinical use of lenzilumab in 12 COVID-19 patients. The manuscript, titled First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe and Critical COVID-19 Pneumonia was published online at medRxiv.org (www.medrxiv.org/content/10.1101/2020.06.08.20125369v1). Patients showed rapid clinical improvement with a median time to recovery of five days, median time to discharge of five days and 100% survival to the data cut-off date. Patients also demonstrated rapid improvement in oxygenation, temperature, inflammatory cytokines and key hematological parameters consistent with improved clinical outcomes.

Dr. Zelalem Temesgen, Professor of Medicine at Mayo Clinic and one of the key authors of the study, said, Lenzilumab use was associated with improved clinical outcomes and oxygen requirement, with no reported mortality. We did not observe any treatment-emergent adverse events attributable to lenzilumab and it was well-tolerated. Based on the pathophysiology of cytokine storm following SARS-CoV-2 infection, along with work conducted at Mayo Clinic on GM-CSF depletion in CAR-T therapy, lenzilumab may offer a rational approach to ameliorate the consequences of cytokine storm in COVID-19.

Dr. Cameron Durrant, chief executive officer of Humanigen, stated, It is extremely encouraging to see this initial group of high-risk patients with severe and critical COVID-19 pneumonia show clinical improvement on lenzilumab, and at the data cut-off point, 11 of them discharged from the hospital. All 12 patients had at least one risk factor associated with poor outcomes, such as age, smoking history, cardiovascular disease, diabetes, chronic kidney disease, chronic lung disease, high BMI, and elevated inflammatory markers, with several patients having multiple such risk factors.

All patients were hospitalized in the Mayo Clinic system and had severe or critical pneumonia as a result of COVID-19. They were also viewed as being at high risk of further disease progression. All patients required oxygen supplementation and had elevation in at least one inflammatory biomarker prior to receiving lenzilumab. All patients had at least one co-morbidity associated with poor outcomes in COVID-19 and several patients had multiple co-morbidities: 58% had diabetes mellitus, 58% had hypertension, 58% had underlying lung diseases, 50% were obese (defined as a BMI greater than 30), 17% had chronic kidney disease and 17% had coronary artery disease. The median age was 65 years.

More details on the companys programs in COVID-19 can be found on the companys website at http://www.humanigen.com under the COVID-19 tab, and details of the Phase III potential registration study can be found at clinicaltrials.gov using ClinicalTrials.gov Identifier NCT04351152.

About COVID-19

COVID-19 is an infectious disease caused by SARS-CoV-2. COVID-19 has become a global pandemic, with almost 8 million confirmed cases and almost 450,000 deaths reported to date. Patients with severe cases of COVID-19 experience severe viral pneumonia that can progress to acute respiratory distress syndrome (ARDS), respiratory failure and death.

In severe and critical patients with COVID-19, published research suggests GM-CSF as the key link between pathogenic Th1 cells and inflammatory monocytes, which secrete additional GM-CSF1. Lenzilumab is a late clinical-stage, monoclonal antibody targeting GM-CSF, a pro-inflammatory cytokine up-regulated in the serum of COVID-19 patients2. The percentages of certain GM-CSF-expressing cells are significantly higher in the blood of ICU-admitted COVID-19 patients compared with healthy controls and are more pronounced in ICU-admitted COVID-19 patients versus non-ICU patients2.

1. Zhou Y, Fu B, Zheng X, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. Pre-Print. 2020. https://doi.org/10.1101/2020.02.12.945576.

2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi:10.1016/s0140-6736(20)30183-5.

About Humanigen, Inc.

Humanigen, Inc. is developing its portfolio of clinical and pre-clinical therapies for the treatment of inflammation and cancers via its novel, cutting-edge GM-CSF neutralization and gene-knockout platforms. We believe that our GM-CSF neutralization and gene-editing platform technologies have the potential to reduce the inflammatory cascade associated with coronavirus infection as well as the serious and potentially life-threatening CAR-T therapy-related side effects while preserving and potentially improving the efficacy of the CAR-T therapy itself, thereby breaking the efficacy/toxicity linkage. The companys immediate focus is to prevent or minimize the cytokine storm that precedes severe lung dysfunction and ARDS in serious cases of SARS-CoV-2 infection and also in combining FDA-approved and development stage CAR-T therapies with lenzilumab, the companys proprietary Humaneered anti-human-GM-CSF immunotherapy, which is its lead product candidate. A potential registrational Phase III study in COVID-19 patients is currently enrolling. The company is also exploring the effectiveness of its GM-CSF neutralization technologies (either through the use of lenzilumab as a neutralizing antibody or through GM-CSF gene knockout) in combination with other CAR-T, bispecific or natural killer (NK) T- cell engaging immunotherapy treatments to break the efficacy/toxicity linkage, including to prevent and/or treat graft-versus-host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). For more information, visit http://www.humanigen.com

Forward-Looking Statements

This release contains forward-looking statements. Forward-looking statements reflect management's current knowledge, assumptions, judgment and expectations regarding future performance or events. Although management believes that the expectations reflected in such statements are reasonable, they give no assurance that such expectations will prove to be correct and you should be aware that actual events or results may differ materially from those contained in the forward-looking statements. Words such as "will," "expect," "intend," "plan," "potential," "possible," "goals," "accelerate," "continue," and similar expressions identify forward-looking statements, including, without limitation, statements regarding our expectations for the Phase III study and the potential future development of lenzilumab to minimize or reduce the severity of lung dysfunction associated with severe and critical COVID-19 infections or to be approved by FDA for such use or to help CAR-T reach its full potential or to deliver benefit in preventing GvHD. Forward-looking statements are subject to a number of risks and uncertainties including, but not limited to, the risks inherent in our lack of profitability and potential need for additional capital to conduct the Phase III study and grow our business; our dependence on partners to further the development of our product candidates; the uncertainties inherent in the development and launch of any new pharmaceutical product; the outcome of pending or future litigation; and the various risks and uncertainties described in the "Risk Factors" sections and elsewhere in the Company's periodic and other filings with the Securities and Exchange Commission.

All forward-looking statements are expressly qualified in their entirety by this cautionary notice. You should not place undue reliance on any forward-looking statements, which speak only as of the date of this release. We undertake no obligation to revise or update any forward-looking statements made in this press release to reflect events or circumstances after the date hereof or to reflect new information or the occurrence of unanticipated events, except as required by law.

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Mayo Clinic Study of Humanigen's Lenzilumab Shows Rapid Recovery and Discharge in Severe and Critical COVID-19 Patients - Business Wire

Cirmtuzumab Plus Ibrutinib Shows Activity and Tolerability in MCL and CLL – OncLive

The combination of the first-in-class humanized monoclonal antibody cirmtuzumab and the BTK inhibitor ibrutinib (Imbruvica) was found to be an active, well-tolerated regimen for patients with relapsed/refractory mantle cell lymphoma (MCL) and treatment-nave or relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from a phase 1b/2 study (NCT03088878).

The trial enrolled patients with relapsed/refractory MCL, or relapsed/refractory or treatment-nave CLL or small lymphocytic lymphoma (SLL) who had measurable disease and had either limited or no prior treatment with BTK inhibitors. The trial is comprised of 3 parts: a phase 1 dose-escalation phase with cirmtuzumab (part 1), an expansion cohort (part 2), and phase 2 randomization of the cirmtuzumab/ibrutinib combination versus ibrutinib alone (part 3).

As of January 29, 2020, 12 patients with relapsed/refractory MCL were enrolled onto part 1 of the trial. All patients had stage III/IV disease at diagnosis and 25% had bulky tumor at the time of study entry. Fifty-eight percent of these patients had Mantle Cell Lymphoma International Prognostic Index risk scores of intermediate or high, and 83% had received 2 prior regimens. Additionally, a total of 34 patients with CLL were enrolled onto either part 1 of the trial (n = 18) or the part 2 expansion phase (n = 16).

Results presented during the 2020 ASCO Virtual Scientific Program by lead author HunJuLee, MD, showed a high tumor response rate with the combination in those with MCL, with an objective response rate (ORR) of 83% and a complete response (CR) rate of 58%. The initial median progression-free survival with the regimen was 17.5 months. Those who had received 1 to 10 months of prior ibrutinib also responded well to the combination; 2 patients achieved CRs and 2 achieved partial responses (PRs).

In patients with CLL/SLL, treatment with the combination led to an overall best response rate of 88% and a clinical benefit rate of 100%. One patient experienced a CR and has since remained in remission for over 8 months and off all CLL treatment. Three other patients achieved PRs with the regimen.

With regard to safety, the most common adverse effects (AEs) potentially related to the combination were fatigue, diarrhea, and contusion. One patient with MCL and 8 patients with CLL reported treatment-related severe AEs. However, the events were thought to be related to ibrutinib or the combination rather than cirmtuzumab alone. Grade 3 or higher AEs included atrial fibrillation (n = 5), pneumonia (n = 3), pericardial hemorrhage, pleural effusion, pyrexia, hyperkalemia, gastrointestinal hemorrhage, and staph infection (n = 1, each).

In terms of medium follow up, it's very short so I don't want to get too excited. The median follow-up was 8 months and the median PFS is 17 months, said Lee. We are very happy with the results we have, and we look forward to building on top of this. There are ways to get rid of MCL but some of the ways that you take have a lot of toxicities involved. It is really exciting that all of my patients did not have any toxicity.

In an interview with OncLive, Lee, an assistant professor of medicine in the Department of Lymphoma & Myeloma and the Jessica and Jeffrey Brue Endowed Professor of Lymphoma Research at The University of Texas MD Anderson Cancer Center, further discussed the interim results of the study examining cirmtuzumab plus ibrutinib and the next steps with this research in MCL and CLL/SLL.

OncLive: Could you provide some background oncirmtuzumaband the rationale to explore it in combination withibrutinibin this setting?

Lee: As you know,the holy grail of cancer therapy is to find a target on the cancer cell that is not expressed on normal cells. Ideally, with lymphomas we're looking for a target on the lymphoma cell that is different from the proteins expressed on the surface of normal B cells. We would like to treat the lymphoma without harming normal B cells. Preclinical studies have examined ROR1, a family of proteins that are expressed in embryonic protein during early life and [then] disappear. [Investigators have] found [that these proteins] were expressed on the lymphoma cells and leukemia cells.[Investigators thought that] if [ROR1] was expressed on malignant lymphoma and leukemia cells and not expressed on normal cells, then it would serve as a great target [for therapy].

Rituximab (Rituxan)was developed in the early 90s and it targets CD20, which is expressed on normal cells. As such, when you give treatments like rituximab, even though the agent is well-tolerated, it does have some collateral damage. Rituximab decreases lymphocyte counts and we do have patients who require intravenous immunoglobulin therapyfollowing prolonged rituximab maintenance [if they have] lowlymphocyte counts.When they observed this finding, investigators questioned whether this is something that can be targetable. However, before we can develop a treatment [we have to understand] what it does.

What they found was that it is 1 of the proliferative survival signals, that are complementary to another system of proteins called immunoglobulin and that is the B-cell receptor. We know that B-cell receptor targeting has been tremendous with the targeting of BTK with ibrutinib and idelalisib (Zydelig). In all these pathways, targeting has generated great treatment options for many of our patients. However, we know that the difficulty withibrutinib, idelalisib, the PI3K inhibitors, and BTK inhibitors, is that they don't [lead to an] 100% complete remission.

Where is it? How are these B cells surviving? What about the patients who are primary refractory? What about the patients who respond initially and then relapse? Where are these cells coming from and where's the survival? We're almost trying to play chess with these lymphoma cells because we know that they're using biological mechanisms to achieve a survival advantage.

[When the BTK is being blocked, these lymphoma cells] reroute the survival signal through another survival channel. We believe one of the mechanisms that this drug works by, is by blocking the ROR1, which is one of the other survival signals. When we gave ibrutinib in preclinical studies, [it was found to] increase the signaling pathway in the ROR1 pathway. If you block the BTK, the cells find an alternative route. The lymphoma and leukemia cells are very smart. They are able to take advantage of alternate sources of growth signals.That's where the idea came in, combined with the results from preclinical studies demonstrating that patients who had high levels of ROR1 had lower survival.

I'm not saying this is the only way that the lymphoma cells escape mechanism. We know that there's mutations in the BTK and so forth and so on. However, this may be one of the contributing factors that help these lymphoma and leukemia cells become resistant to BTK inhibition. Therefore, we feel that blocking this pathway will block both pathways, thus, leading to a deeper response, meaning more CRs.

Could you discuss the design of the trial and the dosing schedules that were investigated?

This was designed as an open-label, phase 1/2 study. We knew that BTK inhibition and the ROR1 works in a complimentary fashion. We already knew the dosing schedule for ibrutinib, but we did multiple-dose escalations to try to find the right recommended dose [forcirmtuzumab] in the phase 2 [portion of the] study. We had 2 mg, 4 mg, 8 mg, 16 mg, 3 kg, and a flat dosing of 300 mg and 600 mg. Ultimately, after the phase 1 study, went with the 600 mg flat dosing, and that was found to be very well tolerated.

This goes right into the safety issue. We're looking for any toxicity. One of the remarkable things about this protein is that many of the antibody-driven therapies have been very well tolerated, andcirmtuzumabhas also been very well tolerated. We did not see any grade 3 toxicity forcirmtuzumab.

Do anti-ROR1 antibodies have an established toxicity profile or is it still under investigation?

That is still under investigation, but in combination with the ibrutinib, we did not have any signal in terms of dose-limiting toxicities with the doses that we gave. Here, at The University of Texas MD Anderson Cancer Center, we gave the 2 mg through 18 mg per kilograms and the high and low flat dosing, and it was found to be very tolerated.

What did we see with efficacy?

The efficacy seen with the combination was very interesting. Two histologies were studied: MCL and CLL. I am leading the MCL side and Michael Choi, MD, of the University of California, San Diego Medical Center, is leading the CLL portion of this study.

The MCL portion showed tremendous, exciting signal on phase 1 and 2 of this study. The ORRs were north of 80%, and the real kicker, knock-your-socks-off data are the CR rates. We were able to get 58% CR rates for many of these very heavily pretreated patients. We had approximately 40% of patients who had undergone autologous stem cell transplantation; we have patients who failed ibrutinib; and we have patients who had received [prior] CAR T-cell therapy and responded. Those findings gets people excited. I was surprised at how good the response was, given that usually toxicity and response go hand in hand. When you get more responses, you usually have very high toxicity. However, we really did not see any grade 3 toxicities.

Tons of CAR T-cells are being developed, but they come with fairly heavy prices. The headlines are big, but I know behind [the scenes], because I take care of these patients. It's not easy; if a patient is 70 years of age, theyre barely getting into the clinic. [When they ask for a CAR T], I get nervous; it is tough. But with this [combination], the majority of my patients [did not even feel that they were on a treatment]. This is very exciting for our patients.

The ORRs were north of 80%, and there was a 58% CR rate. We have 12 patients treated. Part 2 is open and it's accruing very nicely so we're trying to get more patients to enroll. This space is very tight; I'm sure you're aware that MCL is a tough place now because of the success achieved by Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, with ibrutinib and CAR T. We're competing against some big agents, which are very effective. However, it's [a good thing] for our patients, because they have many treatment options that are available.

In terms of CLL, we did see high response rates; however, we did not see the robust CR rates that we saw in MCL; thats one thing to note. They're up to part 2 and that part of the trial is enrolling much faster than MCL. CLL is the most common lymphoid malignancy in North America so investigators are readily finding patients. We're hoping that the enrollment for the MCL portion can get going and will show robust data.

Is there anything that you would like to add?

There was a rapid attainment of CR rates observed. Many of these patients have had hyper-CVAD, autologous stem cell transplantation, and CAR T-cell therapies, among others. [These were not patients who had only received 1 line of prior] therapy. If you start using ibrutinib earlier in treatment, you get higher levels of CRs and higher levels of PFS. However, these are patients that are heavily pretreated with fairly aggressive histologies and behavior. If you look at the waterfall plot, you can clearly see a rapid drop in the tumor sizes of the patients with MCL.

Many more patients were included in the CLL [portion of the study] and they do have a response, but the majority of these responses were PR, so they were not able to attain CR. Although they do have a response, it is not as dramatic as the MCL population.

If you look at the PFS curves for MCL they look nice. It's a very limited population with very limited follow up, so this will need to be followed up for much longer.

This is going to be leading to a very exciting time forcirmtuzumab and ibrutinib as we enroll for part 2 [of the trial], which is going to be the efficacy signal that we will be seeing moving forward. Additionally, other agents are being developed for the ROR1 targets, but the efficacy that we saw in our study with our limited number of patients is very exciting.

Lee HJ, Choi MY, Siddiqi T, et al. Clinical activity of cirmtuzumab, an anti-ROR1 antibody, in combination with ibrutinib: interim results of a phase Ib/II study in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL). J Clin Oncol.2020;38(suppl 15):8036. doi:10.1200/JCO.2020.38.15_suppl.8036

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Cirmtuzumab Plus Ibrutinib Shows Activity and Tolerability in MCL and CLL - OncLive