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American Association for Cancer Research (AACR)

RTX-240, an allogeneic off-the-shelf cell therapy in development by Rubius Therapeutics, is currently being evaluated in a phase 1 trial (NCT04372706) for solid tumors. In data presented recently at the 

2022 American Association for Cancer Research (AACR) meeting

, the agent elicited some responses and prolonged stable disease, according to clinical investigator Alexander I. Spira, MD, PhD, FACP, research institute director with Virginia Cancer Specialists Research Institute and clinical assistant professor at Johns Hopkins.

In a video interview, Spira shared the key takeaways from the AACR presentation and also discussed next steps for RTX-240, including exploring combination treatment alongside pembrolizumab.

The below transcript has been edited for clarity and length.

CGTL: Can you provide some background on RTX-240? How does it work and how is it unique?

Spira: One of the challenges that we know about cellular therapies is both they’re [difficult to] mak[e], they're all kind of personalized, so they take a lot of time to make. There is obviously a huge expense in that...As well as, of course, of the toxicity. Most of the current cellular therapies such as CAR T and allogeneic therapies require hospitalization, a lot of chemotherapy, with very real toxicity and morbidity, so there's a huge desire to come up with a new generation that is both easier, less toxic, and, as we like to say, off-the-shelf, so you can rapidly administer it to patients without this long uptake period.

And that's where RTX 240 comes in. It's rather unique…it's actually a red cell therapy, and the key thing to think about red blood cells is that they don't replicate. So what they've been engineered to do, and these are engineered red blood cells taken from donor cells [from] donor banks, is that they've been engineered to express, in this case, 4-1BBL and IL-15 TP. And the idea here is to use different aspects of the immune system to engage cancer cells and effectively attack them. It's done differently than the typical cellular therapies, which [are] given on a one-time basis; this will be given repeatedly. But of course, most notably, it's off-the-shelf and doesn't necessarily have to be personalized.

CGTL: From the research conducted to date, what has been observed thus far?

Spira: The idea with these cells is that these are supposed to engage NK and T cells, and they've seen some clear evidence of engaging that on the preclinical models, as well as some of the biopsy specimens obtained. In the phase 1 clinical study, and remember, this is a phase 1 clinical study, first-in-human, multiple tumor types, heavily pretreated, some evidence of activity, meaning stabilization of disease, possibly some improvement, again—holding cards close to the chest, not wanting to get too excited—but there's some preliminary evidence of efficacy. The idea now is to take it to patients in earlier lines of therapy, as well as possibly combined with other checkpoint inhibitors such as pembrolizumab or whatever else may come down the pike.

CGTL: What were the primary objectives of the phase 1 trial presented at AACR, and what did patient eligibility look like?

Spira: This [was] very broad…multiple different tumor types were allowed into the clinical study, very heavily pretreated [patients]. These are patients clearly without any options and it's a phase 1 study so the main goals of this were really to explore dose-finding, as well as preliminary evidence of efficacy. One of the important things was getting a lot of biopsies to really look at the preclinical models and see how that matched up with the patients’ specimen. So that was an important end point to look at activity, but really, very broad patient enrollment, [and] really first trying to figure out the dose and then expanding as we get to the higher doses to see what level of efficacy we're able to find. There was also, interestingly, an [acute myeloid leukemia] cohort that I think has previously been reported as well, so looking at multiple different tumor types here.

CGTL: What were some of the primary efficacy findings from the phase 1 trial presented at AACR?

Spira: Some of the key findings, just very high level, of the RTX-240 study presented AACR was some evidence of efficacy, so some prolonged stable disease, what looks like some responses as well. We're able to get to a MTD and come up with a recommended phase 2 dosing as well, which we'll use now going forward. Most importantly, I think it's proof of concept that we're able to give it, not a lot of toxicity, and certainly, obviously, [there’s] a long way between here and…an approved drug, but really showing that this is a viable concept. And not only is [it] a viable concept, but we have good biomarkers to show that [it’s] really doing what you expect it to do, so proof of principle.

CGTL: Have any toxicity concerns been raised so far?

Spira: So far, in terms of looking at toxicity, not really much of anything, so no major concerns whatsoever. One of the things people were concerned about is hemolysis and breaking down the red cell product, obviously, but it's not a ton of red blood cells and we did not see significant hemolysis. Overall, not really many immune-related adverse events either, so incredibly well-tolerated.

CGTL: Part of the phase 2 trial will investigate RTX-240 in combination with pembrolizumab. What's the rationale in combining RTX-240 with that agent?

Spira: The question is obviously why to combine with checkpoint inhibitors? I think a lot of oncology research is now because you can, because they're very well-tolerated as you see. We're almost hard pressed to find a trial that doesn't try a PD-L1 or PD-1 inhibitor. But I think there is a little bit of a scientific rationale here as well, of course, in that you're looking at 2 different aspects of the immune system. So how do you make a cold tumor hot? How do you attack things from multiple aspects? And clearly, as you think about a development path, as you think about things down the road, such as first-line lung cancer, they'll have to be combined with another drug because that's where we are right now. And most importantly, we don't think, at least now. [that] there's going to be a lot of overlapping toxicity, meaning that you can combine the 2 together. So a couple of reasons… One, both scientifically, and two, a practical rationale a s we get these drugs closer to approval, we hope.

CGTL: What are the next steps in the development of RTX-240?

Spira: I think a couple of things from that standpoint. One is, what is going to be the efficacy in a less heavily pretreated population? That's the fundamental question. [In] what tumor types do we take it forward? I think there's a plan to take it forward in lung right now. But what are the tumor types down the road? No. 2, this is also a unique platform, right? It's not just RTX-240. And Rubius, the company that's making this, actually has a couple of trials already, because you have a platform, right? So you have the red blood cells, but now you can transfect with multiple different targets. There’s one for HPV-positive tumors, there's another one being done right now also in phase 1 escalation...So there's a lot of different things you can do, not only in terms of RTX-240, but with this platform as well. Kind of like, as I like to say, antibody-drug conjugates, you can mix and match and do multiple different things so it gets to be exciting. But first things first, let's see some activity.

CGTL: If ultimately approved, how do you see RTX-240 fitting into the treatment landscape in the future?

Spira: Like most things…we think…what's the path to development? Second-line is, of course, the first area of development because that's where most drugs are developed. But obviously, there's some thoughts, what can you do in first-line, right? Because these are patients…if it doesn't have a lot of toxicity, although we've made a lot of headway in terms of first-line response rates…there's still room for improvement. So how do we improve on that, as well as of course, in the second-line, and I think that'll be the developmental question, as we see how things play out with larger phase 2 studies.

CGTL: What is the take-home message for clinicians?

Spira: In terms of take-home messages regarding RTX-240, I actually want to take a bigger 30,000-foot view. There's been a lot of time and energy put on cellular therapies and cellular therapies have not panned out as we'd like them to…because of the delay in making them. There are some great studies out there, but they require a huge amount of expense, work, and time, and sometimes as you try and get this personalized therapy, solid tumor patients don't have that time. And we have not had any home runs. Right now, there's been some hints of activity, but I think we would all agree that in the solid tumor world, the data has not been as good as the hematologic malignancies.

For all those reasons, I think we need a new platform. From my standpoint, the most exciting thing is what things can be done off-the-shelf that we can get to patients rapidly, [that are] less of an expense, that we don't have to wait for these personalized therapies that also have a different mechanism of action and, most importantly, may work.

CGTL: Are there any other cell therapy products in development that you are excited about and would like to discuss?

Spira: In terms of other things and where Rubius is going, they have a couple of other exact things based on this platform. They have one for HPV-positive tumors, and they have another immune stimulant as well, both in early phase 1 clinical studies. They're doing what we kind of expected [and] using this red cell platform and, as you can figure out how to scale up, you can literally come up with any mechanism of action. So one is, how much better is that going to be? You can put PDL on these drugs and see if it can stimulate using PDL therapies, or is it really going to be guided for newer therapies or in combination as well? It’s literally, as I said, you can mix and match and come up with any sort of thing based upon what you find. You can imagine things such as even acting as an antibody-drug conjugate...Instead of using an ABC, putting the antibody in the cell surface and doing it that way as well, so there's a host of things that you can do. Obviously, it'll depend on how many red cells you can administer, the mass, how it gets to the tumors, etc., but it's really a very interesting concept. Hopefully, [it’ll] be the next generation of cellular therapies, which is what we need.

Alexander I. Spira, MD, PhD, FACP, research institute director with Virginia Cancer Specialists Research Institute, discusses the examination of RTX-240 in a phase 1 trial (NCT04372706) with solid tumors, presented recently at the 2022 AACR Annual Meeting. 

Takeaways From Phase 1 Trial of RTX-240 in Solid Tumors: Alexander I. Spira, MD, PhD, FACP

Investigators shared details of the ongoing phase 1a/b NEBULA trial (NCT05043714) exploring the use of NG-641, a novel adenoviral vector, in combination with nivolumab (Opdivo) in a population of patients with previously treated metastatic or advanced epithelial tumors. The presentation took place at the recent 

2022 American Association for Cancer Research (AACR) Annual Meeting

The open-label, dose-escalating trial is investigating the safety and preliminary efficacy of NG-641, a next-generation blood-stable and transgene-armed T-SIGn adenoviral vector. T-SIGn vectors allow for intravenous administration for selective infection of cancer cells as well as replication at tumor sites. Activated immune cells from the therapy support functional anti-tumor responses.

The agent expresses 4 immunostimulatory transgenes and works by crosslinking T cells to fibroblast activating-protein–positive cancer-associated fibroblasts, which activates the immune system. Additionally, CXCL9 and CXCL10 induce T-cell migration and interferon-α2 enhances T-cell activation and induces the killing of cancer cells by tumor antigen–specific T cells.

Already, NG-641 has shown encouraging preliminary safety and tolerability results in the ongoing phase 1a dose-escalation STAR trial (NCT04053283), which is a first-in-human study for the gene therapy.

When used in combination with nivolumab in the NEBULA study, the regimen is expected to result in complementary mechanisms of action.

Patients with metastatic or advanced epithelial cancers who have received prior anti–PD-1/PD-L1 therapy, have measurable disease, an ECOG performance status, adequate lung reserve, and adequate organ and bone marrow function are eligible to enroll in the trial. The included tumor types are urothelial carcinoma, squamous cell carcinoma of the head and neck, microsatellite instability–high or mismatch repair deficient cancers, non–small cell lung cancer, uterine or endometrial cancer, cervical cancer, esophageal cancer, gastric cancer, triple-negative breast cancer, cutaneous squamous cell carcinoma, hepatocellular carcinoma, and tumor mutational burden–high tumors.

Those with active infections, viral disease, autoimmune disease, acute kidney injury, renal impairment, or interstitial lung disease as well as patients with risk factors for bleeding or clotting events, bowel obstruction, or tumor flare are ineligible to participate in the trial.

A total of 30 patients are expected to be enrolled in the phase 1a portion of the trial, which consists of 5 escalating dose levels in a Bayesian Optimal Interval design. Phase 1b is the dose-expansion stage of the trial, which will consist of tumor-specific cohorts.

Dose level –1 is an intravenous infusion of NG-641 at 6 x 10

 virus particles (vp) given on days 1, 3, and 5; dose level 1 is 1 x 10

 vp of NG-641 on days 1, 3, and 5; dose level 2 is 1 x 10

 vp on days 3 and 5; dose level 3 is 1 x 10

 vp on days 3 and 5; and dose level 4 is 1 x 10

 vp on days 3 and 5. Across all dose levels, nivolumab will be administered at 480 mg on day 15 of the 4-week cycle.

The primary end point of the NEBULA trial is safety and tolerability as well as the recommended dose of the regimen. The secondary end point is preliminary antitumor activity. Additionally, pharmacokinetics, immunogenicity, and pharmacodynamics will be assessed using tumor tissue and blood samples.

Enrollment to the first cohort is currently ongoing in the United States at the UCLA Medical Center and in the United Kingdom at The Clatterbridge Cancer Centre, Oxford University Hospitals.

Lillie T, Parkes E, Ottensmeier C, et al. A multicenter phase 1a/b study of NG-641, a tumor-selective transgene-expressing adenoviral vector, and nivolumab in patients with metastatic or advanced epithelial tumors (NEBULA). Presented at: AACR Annual Meeting 2022; April 8-13, 2022; virtual. Abstract CT214. https://bit.ly/3xoXv1A

Exploring NG-641 Plus Nivolumab for Previously Treated Metastatic or Advanced Epithelial Tumors

Patients with diffuse intrinsic pontine glioma (DIPG) and spinal diffuse midline glioma (sDMG) experienced clinical benefit after treatment with sequential intravenous (IV) and intracerebroventricular (ICV) infusion of GD2-chimeric antigen receptor (CAR) T-cell therapy.

These results, from a phase 1 study (NCT04196413), were presented at the 

, April 8-13, 2022, in New Orleans, Louisiana, by Robbie G. Majzner, MD, assistant professor of pediatrics, division of hematology and oncology, Stanford University.

The phase 1, dose escalation trial has enrolled 13 participants, 11 of which were treated after 2 were removed due to rapid progression. Four patients (3 with DIPG and 1 with H3K27M sDMG) were treated with IV GD2-CAR Tat the lower dose level (1x10

/kg), and 9 (7 with DIPG and 2 with sDMG) were treated at the higher dose level (3x10

/kg) following lymphodepletion. All ICV infusions were at the same dose level of 10-30e6 GD2-CAR T-cells and occurred every 4 to 8 weeks for a maximum of 12 doses after IV infusion.

Nine of 10 evaluable patients experienced radiographic and/or clinical benefit after IV infusion and subsequently received a median of 4 ICV infusions (range, 1-6). Four patients continue to receive ICV infusion with continued clinical and radiographic benefit observed at 7, 8, 9.5, and 11 months. Notably, a 31 year old patient with sDMG experienced at least a 95% tumor volume reduction and a 17 year old patient with DIPG experienced at least a 98% pontine tumor volume reduction.

“Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CAR T without LD. Patients are eligible for up to 12 ICV infusions of GD2-CAR T administered every 4-6 weeks. Clinical benefit will be formally assessed using patient-reported outcomes. GD2-CAR T has the potential to transform therapy for patients with H3K27M+ DIPG/sDMG,” Majzner and colleagues wrote.1

The lower dose was generally well-tolerated, with no dose-limiting toxicities (DLTs). The higher dose level yielded 3 cases (2 DIPG, 1 sDMG) of grade 4 cytokine release syndrome (CRS) although these were successfully managed with tocilizumab, anakinra, and corticosteroids. All participants experienced transient tumor inflammation-associated neurotoxicity (TIAN) managed with anakinra, cerebrospinal drainage, or dexamethasone. ICV infusions were not associated with high-grade CRS although transient cases of fever, meningismus, headache, TIAN, nausea, and/or vomiting did occur.

Majzner and colleagues previously reported data from the first 4 patients treated in a paper published in 

These patients were treated at the lower dose level and thus many toxicities observed at the higher dose level were not observed.

“The promising early experience with GD2-CAR T cells for DIPG and spinal cord DMG described here sets the stage for further optimization of this approach for this historically lethal CNS cancer. This clinical trial will continue to treat patients with H3K27M+ DIPG and spinal DMG using GD2-CAR T-cell therapy to determine optimal dose, route and schedule, and to determine efficacy,” Majzner and colleagues wrote in 

1. Majzner R, Mahdi J, Ramakrishna S, et al. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells. Presented at: AACR Annual Meeting, April 8-13, 2022; New Orleans, Louisiana.
2. Majzner RG, Ramakrishna S, Yeom KW, et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature. 2022, 603: 934-941. doi:10.1038/s41586-022-04489-4

While the lower IV dose was generally well-tolerated, the higher dose yielded cases of serious cytokine release syndrome. 

GD2-CAR T-Cell Therapy Yields Clinical Benefit in Glioma

The allogeneic chimeric antigen receptor (CAR) T-cell therapy TruUCAR GC502 has demonstrated promising efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL).

These data, from an ongoing phase 1 investigator-initiated trial, were presented at the 

, April 8-13, 2022, in New Orleans, Louisiana, by Xinxin Wang, PhD, vice president, research and development, Gracell.

"As an allogeneic, off-the-shelf CAR-T therapy, GC502 has the potential to provide patients who may not be eligible for autologous CAR-T therapy with hope to achieve a deep response,” Martina Sersch, MD, chief medical officer, Gracell, said in a statement.

GC502 is a CD19/CD7 dual directed CAR and contains a T cell enhancer and genetically disrupted TRAC and CD7 loci to avoid graft versus host disease (GvHD) and fratricide. The therapy is manufactured using leukopaks from human leukocyte antigen-unmatched healthy donors.

Four patients have been enrolled in the study, which continues to recruit participants, and treated with doses of 1.0x10

 cells/kg of 1 of 2 different formulations (A and B) of GC502. Patients were lymphodepleted by fludarabine and cyclophosphamide prior to infusion. Patients ranged from 15 to 34 years of age, were heavily pretreated, and had received either autologous or allogeneic CD19 or CD19/CD22 targeted CAR-T therapy. They had a median of 48.1% baseline marrow blast levels (range, 19.5-92). One patient had extramedullary involvement.

As of January 28, 2022, all patients had received a single dose of GC502. One patient received the lower dose level and 3 received the higher. Three patients were evaluable at 28 days after treatment and 2 of these had achieved a complete response (CR). One patient achieved a partial response (PR) and subsequently received hematopoietic stem cell transplantation on day 39.

Treatment-related adverse events (TEAEs) did occur, with 2 cases of grade 3 febrile neutropenia, 1 case of grade 4 thrombocytopenia, and 3 cases of grade 3 anemia in the 3 evaluable patients. These TEAEs resolved after standard of care treatment. Other TEAEs included 3 cases of at least grade 3 γ-glutamyl transferase elevations, 2 cases of at least grade 3 aspartate aminotransferase elevations, and 3 cases of at least grade 3 alanine aminotransferase elevations.

Grade 2 cytokine release syndrome (CRS) occurred in 2 patients treated with formulation B of GC502 while grade 3 CRS occurred in 2 patients treated with formulation A (duration, 7 and 10 days). These cases were manageable and resolved after treatment with ruxolitinib, SOC and supportive care. Investigators observed no cases of immune effector cell-associated neurotoxicity syndrome or acute GvHD were observed.

Investigators assessed cellular expansion and found that the patient treated at the lower dose level did not show adequate GC502 cellular expansion. In the second dose level, peak expansion in peripheral blood was observed between week 1 to 2. Median peak CAR copies were 149,945 copies/ug DNA (range 10,849-195,400).

“The early results show the potential of GC502 and warrant further evaluation in the ongoing clinical investigator-initiated-trial. Being the second product candidate from our allogeneic TruUCAR platform, GC502 further validates TruUCAR's platform approach and potential wide applicability,” Sersch added.

1. Li S, Wang X, Yuan Z, et al. Early results of a safety and efficacy study of allogeneic TruUCAR™ GC502 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Presented at: 2022 American Association for Cancer Research Annual Meeting. April 8-13, 2022; New Orleans, Louisiana. Abstract CT196/21.
2. Gracell Biotechnologies to Present Data at AACR Annual Meeting 2022 Showcasing Early First-in-Human Results for GC502 in r/r B-ALL. News release. Gracell Biotechnologies. April 8, 2022. https://ir.gracellbio.com/news-releases/news-release-details/gracell-biotechnologies-present-data-aacr-annual-meeting-2022

The phase 1, investigator-initiated trial continues to recruit participants with B-ALL. 

Allogeneic CAR T-Cell Therapy Shows Promise in R/R B-Cell Acute Lymphoblastic Leukemia 

A novel combination approach that includes an autologous CAR T-cell therapy and a CAR T-cell amplifying RNA vaccine has shown preliminary efficacy in patients with advanced solid tumors. Data on BNT211 from the ongoing phase 1 /2a trial were presented at the 

2022 American Association for Cancer Research Annual Meeting

, April 8-13, 2022, in New Orleans, Louisiana.

The combination regimen from COVID-19 vaccine player BioNTech utilizes a CAR T-cell product that targets tumor specific antigen claudin 6 (CLDN6)-positive solid tumors and a CAR T-cell amplifying RNA vaccine, CARVac, that helps improve CAR T-cell therapy persistence and functionality. The combination is currently being explored in an ongoing 2 part, phase 1/2a dose escalation trial (NCT04503278) in heavily pretreated patients with a median of 4 to 5 prior lines of treatment with CLDN6-positive relapsed or refractory advanced solid tumors, with a target enrollment of 36 participants.

As of the data cutoff, 16 patients were treated in the dose level 1 (1x10

 CAR-T cells) groups alone (n=9) or combined with CARVac (n=7), which is administered every 3 weeks for 5 treatments, followed by a maintenance dose administered every 6 weeks. Generally well tolerated, investigators observed 37 ≥ Grade 3 adverse events (AEs) related to the drug product, including cytopenia and asymptomatic transaminase and lipase elevations. Two dose-limiting toxicities were reported: grade 4 cytopenia in part 1 of dose level 2 and grade 4 hemophagocytic lymphohistiocytosis at part 2 of dose level 2. Notably, based on the observance of prolonged cytopenia in patients with testicular cancer with a history of high-dose chemotherapy and stem cell transplant, a reduced lymphodepletion cohort has been launched. Low-grade cytokine release syndrome was observed in 8 patients without any signs of neurotoxicity.

Peripheral blood analysis revealed robust CAR T-cell engraftment of near 10

 total counts, peaking around day 17. Six weeks post-infusion, 6 of the 14 evaluable participants showed a partial response (4 with testicular cancer and 2 with 

) with a 39% to 49% shrinkage of target lesions, and 5 had stable disease with evidence of shrinkage of target lesions, with an overall response rate of 43% and a disease control rate of 86%. Notably, 1 patient showed no change and 2 were progressing. At 12-week follow-up, 4 of the 6 patients with PR showed a deepening and durability of response (50%-73% shrinkage), and 1 patient reached complete response at 18 weeks (dominant EMRA phenotype of transferred CAR T-cells and persistence of more than 150 days post-infusion).

Patients with testicular cancer in the dose-level 2 group (n=4) had disease control, and 3 had objective responses. One testicular cancer patient in part 2 of the dose-level 1 group who received the reduced lymphodepletion did show a partial response. Overall, more robust antitumor activity was observed in the higher dose level group when combined with CARVac, with 4 of 5 patients showing a partial response.

“Claudin-6 was never targeted with cellular therapy before, but in this study, the approach is already showing an efficacy that may be better than the data from other CAR-T trials in solid tumors,” said John Haanen, MD, PhD, principal investigator and medical oncologist at the Netherlands Cancer Institute in Amsterdam, Netherlands.

 “While the data are very early, it is remarkable that all patients with testicular cancer showed clinical benefits at dose level 2, and the responses we have observed can be deep, including one ongoing complete remission. I look forward to further evaluating this exciting new modality for solid tumor patients.”

BioNTech expects to read out additional data from the ongoing trial in the second half of this year.

1. Haanen JB, Mackensen A, Koenecke C, et al. BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors. Presented at: 2022 American Association for Cancer Research Annual Meeting. April 8-13, 2022; New Orleans, Louisiana. Abstract CT002.

2. BioNTech Presents Positive Preliminary Phase 1/2 Data for First-in-Class CAR-T Program BNT211 at AACR. News release. BioNTech. April 11, 2022. 

https://investors.biontech.de/news-releases/news-release-details/biontech-presents-positive-preliminary-phase-12-data-first-class

The novel regimen from BioNTech demonstrated encouraging results in patients with testicular or ovarian cancer.  

Combination CAR T-Cell Therapy, RNA Vaccine Shows Efficacy in Solid Tumors 

Affimed’s innate cell engager therapy, AFM13, has demonstrated promising efficacy in patients with CD30-positive, 

when precomplexed with cord blood (CB)-derived natural killer (NK) cells.

Positive data from a phase 1 trial (NCT04074746) being conducted at MD Anderson Cancer Center were presented at the 

American Association for Cancer Research (AACR) Annual Meeting

, April 8-13, 2022, in New Orleans, Louisiana, by first author Yago Nieto, MD, PhD, professor, department of stem cell transplantation, division of internal medicine, The University of Texas MD Anderson Cancer Center.

“The data that we report today are highly encouraging. All patients on this trial were refractory to all available treatment options. Still the combination of AFM13 and precomplexed NK cells resulted in a 100% response rate and a 62% rate of complete responses. We are excited to see a deepening of responses from partial responses to complete responses with a second cycle and have amended the study to allow patients to receive additional cycles, which may further increase the efficacy,” Andreas Harstrick, MD, chief medical officer, Affimed, said in a statement.

“To our knowledge, this is the highest response rate reported so far in Hodgkin Lymphoma patients with treatment-refractory disease.”

AFM13 is a first-in-class CD30/CD16a bispecific antibody construct. In this small, academic, phase 1 trial, the therapy was combined with IL-2/IL-15/IL-18 preactivated and expanded CB-derived NK cells prior to infusion.

This combination demonstrated greater activity than AFM13 alone.

 First Patient Dosed With Angiocrine’s Reparative Cell Therapy for Lymphoma Treatment Regimens

Nineteen patients have been treated in the study to date; these patients had a median age of 37 years (range, 20-68), were mostly male (n = 13), had a median of 6 prior lines of therapy (range, 1-14), and a median of 5 (range, 1-14) prior relapses or progressions of disease. Study participants received 2 cycles of fludarabine/cyclophosphamide prior to AFM13-CB NK cell infusion followed by weekly infusions of AFM13. CB NK cells expanded as early as 3 days after infusion and persisted for up to 1 month.

Patients have been treated in 3 dose levels, 106 NK cells/kg (n = 3), 107 NK cells/kg (n = 3), and 108 NK cells/kg (n = 13). All patients had active, progressive disease at enrollment and no patients received bridging therapy. Cords were not selected according to human leukocyte antigen match, which was 0/6 (n = 16), 1/6 (n = 17), 2/6 (n = 2), 3/6 (n = 1), and 4/6 (n = 1).

Investigators reported 17 responses to therapy, including 8 complete responses (CR) and 9 partial responses (PR). There were 2 cases of progressive disease. All patients treated at the third dose level, which is the recommended phase 2 dose, responded with 6 CRs and 7 PRs. Two patients received an autologous stem cell transplant after treatment. Progression-free survival was 58% at a median follow-up of 6 months (range, 2-16) and overall survival was 79%.

The therapy was well-tolerated, with no cases of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft –versushost disease. There were 6 infusion-related reactions, 1 of which was grade 3 and 5 of which were grade 2, in 110 infusions of AFM13 alone with no reactions to the complexed AFM13-NK cell infusion.

“A year ago, we were struck with hopeful optimism when the first four patients in the study all showed a response. Now, we are again presenting data at AACR and the results not only hold strong in a larger patient population but also show an increasing number of CRs with early but encouraging durability,” Adi Hoess, MD, PhD, chief executive officer, Affimed, added to the statement.

“These ongoing successes with AFM13 represent an important milestone for Affimed and could mark a turning point in the innate immuno-oncology space, potentially setting the stage for expanding this approach to additional cancer indications. Our goal is to leverage the distinct features of our ROCK platform to generate best-in-class ICE molecules that drive effective innate immune cell activation for the benefit of broad patient populations, addressing hematologic and solid tumor malignancies.”

Affimed is currently conducting the phase 2 REDIRECT registrational study (NCT04101331) of AFM13 alone in R/R CD30-positive T-cell lymphoma or transformed mycosis fungoides, which completed enrollment in 2021. Topline data from the trial is expected to be read out in the second half of 2022.

1. Nieto Y, Banerjee P, Kaur I, et al. Innate cell engager (ICE®) AFM13 combined with preactivated and expanded cord blood (CB)-derived NK cells for patients with refractory/relapsed CD30+ lymphoma. Presented at: 2022 American Association for Cancer Research Annual Meeting. April 8-13, 2022; New Orleans, Louisiana. Abstract CT003.
2. Affimed presents updated clinical data from phase 1/2 study of AFM13 precomplexed with cord blood-derived NK Cells At AACR Annual Meeting. News release. Affimed. April 10, 2022. https://www.affimed.com/affimed-presents-updated-clinical-data-from-phase-1-2-study-of-afm13-precomplexed-with-cord-blood-derived-nk-cells-at-aacr-annual-meeting/

AFM13 is currently also being evaluated on its own in lymphoma in a phase 2 registrational study. 

Cord Blood Combined Natural Killer Cell Engager Therapy Shows Efficacy in Lymphoma 

The chimeric antigen receptor (CAR)-expressing natural killer (NK) cell therapy iCAR-ILC-N101 seems to be well-tolerated in 1 patient with ovarian clear cell carcinoma (OCCC) dosed so far in a first in-human phase 1 clinical trial being conducted in Japan.

, April 8-13, 2022, by first author Kenichi Harano, MD, National Cancer Center Hospital East Japan.

“...There is theoretically no risk of developing graft-versus host disease because the product does not have a T-cell receptor. The product has a relevant living period in the body, thereby has little concern about residual toxicity and reduces systemic side effects by topical treatment,” Harano and colleagues wrote.

The phase 1 trial is evaluating the safety, toxicity, and efficacy of CAR-ILC-N101 in patients with histologically diagnosed glypican-3 (GPC3)-positive advanced or recurrent OCCC with peritoneal dissemination. Patients must be resistant to standard therapy and have matched HLA-A24 or B52.

One patient was enrolled in July 2021 in the lowest of 3 dose cohorts (0.5x106 cells/kg, 1x106 cells/kg, 3x106 cells/kg) and has been dosed. No dose-limiting toxicities have been observed. The therapy is administered intraperitoneally weekly for 4 weeks. The first patient in each cohort will be observed for 14 days for safety after the first treatment and then receive iCAR-ILC-N101 on days 15 and 22.

The allogeneic iCAR-ILC-N101 therapy is a human leukocyte antigen-homozygous induced pluripotent stem cell-derived, CAR-expressing, GPC3-targeted, innate lymphoid cells/NK cell (ILC/NK) therapy. GPC3 is expressed in hepatoblastoma, hepatocellular carcinoma, and OCCC but not normal tissue. It contains both antigen-specific and NK activating receptor-mediated cytotoxicity and is designed to overcome limitations of autologous CAR T-cell therapies or NK cell therapies.

Intraperitoneal injection of iCAR-ILC-N101 has previously shown efficacy in preclinical studies in GPC3-positive, ovarian tumor-bearing, immunodeficient mouse models. Investigators observed suppressed tumor growth in these models.

“Intraperitoneal administration of iCAR-ILC-N101 is expected to show antitumor activity for OCCC patients with peritoneal dissemination that express GPC3 and reduce systemic side effects, thereby ensuring safety and improving therapeutic efficacy,” Harano and colleagues wrote.

Harano K, Kaneko S, Nakatsura T, et al. First in human trial of off-the shelf iPS derived anti-GPC3 NK cells for recurrent ovarian clear cell carcinoma with peritoneal dissemination. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022. Abstract #5185

The first in-human phase 1 clinical trial is being conducted in Japan. 

Trial Evaluating CAR-NK Cell Therapy in Ovarian Clear Cell Carcinoma 

“Right now, it's really difficult to make [cell therapies], it's very complicated in where you can and can't administer them and people are very constrained in what they can make them do. But if you can solve that fundamental problem of how do you tell a cell what to become, and how do you manufacture it in a scalable way, there's many different diseases that one can pursue and you should be able to implement it in a way that's very patient friendly. So, eliminating the need for preconditioning or hospitalization.”

SQZ Biotech’s novel approach to creating cell therapies relies on their proprietary Cell Squeeze technology to temporarily disrupt cell membranes and allow the entry of the biologic cargo, differentiating them from many emerging cell therapies that rely on viral vectors and multi-step manufacturing processes.

 The company hopes that this relatively simple approach may cause less dysfunction to the altered cells allow and for a wider application of cell therapies.

spoke with Armon Sharei, PhD, founder and chief executive officer, SQZ, to learn more about the company’s technologies, including their Antigen Presenting Cell (APC) Platform created via Cell Squeeze that can be used to activate killer T-cell responses. He stressed how the ease of manufacturing offered by the Cell Squeeze technology allows for easy switches between antigens in creating APCs that can work against different targets.

Recent preclinical data presented at the 

American Association for Cancer Research (AACR) 2021 Annual Meeting

, April 9-14, 2021, showed that SQZ-enhanced antigen-presenting cells demonstrated meaningful increases in CD8 T-cell response through incorporating costimulatory molecules and cytokine signaling.

 Sharei touched on these data and discussed further data on the APC platform to be presented in the upcoming year.

1. Our Technology. SQZ Biotech. https://sqzbiotech.com/our-technology/
2. SQZ Biotech presents preclinical data on its mRNA-based enhanced APCs and the potential of the SQZ APC platform in KRAS driven tumors. News release. SQZ Biotech. April 10, 2021. https://www.businesswire.com/news/home/20210410005002/en/SQZ-Biotech-Presents-Preclinical-Data-on-its-mRNA-based-enhanced-APCs-and-the-Potential-of-the-SQZ-APC-Platform-in-KRAS-Driven-Tumors

The founder and chief executive officer of SQZ Biotech discussed the potential of their APC platform to treat a variety of tumors. 

Making Antigen-Presenting Cells With Cell Squeeze Technology

"SQZ is such a simple system that it seems to work across every cell type that we try and we can deliver a whole wide range of different materials. Ultimately that means we can go after a lot of biologies that were hard in the past. So, from a patient perspective, that expands what you can implement this for and solves that problem as far as the biologies.”

Unlike many emerging cell therapies that rely on viral vectors and multi-step manufacturing processes, SQZ Biotech’s approach uses their proprietary Cell Squeeze technology to temporarily disrupt cell membranes and allow the entry of the biologic cargo.1 The company hopes that their relatively simple approach may allow for a wider application of cell therapies and cause less dysfunction to the altered cells.

spoke with Armon Sharei, PhD, founder and chief executive officer of SQZ to learn more about the development of Cell Squeeze technology and its potential to be more widely used than traditional cell therapy approaches. He discussed the limitations of cell therapies currently using electroporation or viral transfection and stressed the simplicity of Cell Squeeze and its greatly reduced turn-around time that allows for efficient and accessible manufacturing of therapies.

He also touched on the recent preclinical data presented at the American Association for Cancer Research (AACR) 2021 Annual Meeting, April 9-14, 2021, which showed that SQZ-enhanced antigen-presenting cells demonstrated meaningful increases in CD8 T-cell response through incorporating costimulatory molecules and cytokine signaling.2


2. SQZ Biotech presents preclinical data on its mRNA-based enhanced APCs and the potential of the SQZ APC platform in KRAS driven tumors. News release. SQZ Biotech. April 10, 2021. https://www.businesswire.com/news/home/20210410005002/en/SQZ-Biotech-Presents-Preclinical-Data-on-its-mRNA-based-enhanced-APCs-and-the-Potential-of-the-SQZ-APC-Platform-in-KRAS-Driven-Tumors

The founder and chief executive officer of SQZ Biotech discussed the development and advantages of their proprietary Cell Squeeze technology in creating cell therapies. 

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