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Society for Immunotherapy of Cancer (SITC)

“We envision Tmod being a game changer for immunotherapy because it allows you to do personalized treatment... it's tailoring the treatment of a patient’s cancer using immunotherapy to their particular tumor type.”

A2 Biotherapeutics presented data on the observational BASECAMP-1 study (NCT04981119) and preclinical data on mesothelin (MSLN) and carcinoembryonic antigen (CEA)-targeted Tmod chimeric antigen receptor (CAR) T-cell therapies at the 

36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), November 10-14, 2021

Tmod cell therapies were efficacious in preclinical studies. The BASECAMP-1 study is identifying patients with relapsed solid tumors with human leukocyte antigen (HLA) loss of heterozygosity (LOH) as future recipients of Tmod cell therapy.

 HLA LOH is present in approximately 13% of all solid tumors and up to 33% of pancreatic cancers. The study is also assessing leukapheresis and manufacturing feasibility for future Tmod therapies. 

 spoke with Molina to learn more about developing personalized immunotherapies for solid tumors and the value of HLA LOH in targeting these tumors.

1. A2 Bio to Highlight Program Updates in Two Presentations at SITC 2021. News release. A2 Bio Therapeutics. November 1, 2021. https://www.businesswire.com/news/home/20211101005077/en/A2-Bio-to-Highlight-Program-Updates-in-Two-Presentations-at-SITC-2021
2. Molina J, Go W, Kopetz S, et al. BASECAMP-1: an observational study to identify relapsed solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) and leukapheresis for future CAR T-cell therapy. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 491.

The hematologist/oncologist from Mayo Clinic discussed targeting HLA loss in solid tumors. 

Treating Solid Tumors With Personalized Immunotherapy: Julian Molina, MD, PhD 

“It's important to go to sites of reference - places that are more familiar with [cell therapies] and the kind of toxicities that may occur, so the patient has the best outcome. But, our goal for the future is that these therapies that can be given even in small towns and are available everywhere.”

Mesothelin (MSLN) and carcinoembryonic antigen (CEA)-targeted Tmod chimeric antigen receptor (CAR) T-cell therapies may hold promise in treating solid tumors, according to ositive preclinical feasibility data presented at the 

To further explore the potential of these therapies, the observational BASECAMP-1 study (NCT04981119), data on which were also presented at SITC 2021, is identifying patients with relapsed solid tumors with human leukocyte antigen (HLA) loss of heterozygosity (LOH) as future recipients of Tmod cell therapy.

 HLA LOH is present in approximately 13% of all solid tumors and up to 33% of pancreatic cancers. The study is also assessing leukapheresis and manufacturing feasibility for future Tmod therapies.

 spoke with Molina to learn more about the challenges of cell therapy and immunotherapy in the solid tumor setting and how Tmod cell therapies may address these challenges.

The hematologist/oncologist from Mayo Clinic discussed advantages of Tmod cell therapy in solid tumors. 

Challenges of Cell Therapy in Solid Tumors: Julian Molina, MD, PhD

“The big advantage of the Tmod technology is that it's a way to selectively target cancer cells. And again, this approach is so unique in the way that in the same construct, you are able to modulate this expression: you're able to have a blocker and you are able to have an activator to use depending on what the cancer cells express.”

Data on the observational BASECAMP-1 study and preclinical data on Tmod chimeric antigen receptor (CAR) T-cell therapies were presented at the 

, by Julian Molina, MD, PhD, professor, oncology, Mayo Clinic.

Mayo Clinic and A2 Biotherapeutics are partnering to develop mesothelin (MSLN) and carcinoembryonic antigen (CEA)-targeted TmodCAR T-cell therapies. Preclinical data has demonstrated the technology’s robust protective effect on surrogate normal human cells in vitro, even in mixed-cell populations, while also yielding a robust cytotoxic effect on tumor cells in xenograft models.

The BASECAMP-1 study is being conducted to identify patients with relapsed solid tumors with human leukocyte antigen (HLA) loss of heterozygosity (LOH) as a future target for Tmod cell therapy.

 spoke with Molina to learn more about Tmod technology and how it compares to other T-cell therapies. He discussed advantages of the technology in solid tumors.

The hematologist/oncologist from Mayo Clinic discussed advantages of Tmod technology in solid tumors. 

Improving Specificity of T-Cell Therapies in Solid Tumors: Julian Molina, MD, PhD

IMA203, an autologous, TCR-engineered T cell (TCR-T), PRAME-directed therapy from Immatics has demonstrated efficacy across multiple types of solid cancers, according to data from the IMA203 phase 1 trial (NCT03686124).

 The personalized cell therapy is developed using Immatics’ ACTengine.

These data, based on 16 heavily pre-treated patients in the IMA203 trial, were presented at the 

, by investigator Martin Wermke, MD, University Hospital Dresden.

Investigators found that all 12 evaluable patients achieved disease control, defined as stable disease (SD) or a partial response (PR), with 6 patients demonstrated PRs according to RECIST1.1. The therapy had an acceptable safety profile, with only transient and manageable treatment-emergent adverse events (AEs). 

 spoke with Cedrik Britten, MD, chief medical officer, Immatics, to learn more about IMA203 and what differentiates the candidate from other cell therapies. He also discussed how IMA203 could improve outcomes in patients with solid tumors.

 How does IMA203 compare to other cell therapies and what are its advantages in solid tumors?

While other cell therapies mostly focus on improving the interaction of the T cell with the tumor cell and can only target peptides present on the cell surface, Immatics has established a screening technology that is able to identify tumor-specific peptides derived from proteins within the cancer cell. This increases the cancer target space by approximately 300%. After identification and validation of the cancer target, Immaticsis able to engineer T cells designed to specifically target and destroy these tumor cells. Combining screening for the right targets and modification of the T cell maximizes specificity and efficacy of our therapeutic approach.

For the cell therapy approach with IMA203, Immatics is utilizing TCR-T cells optimized for targeting a peptide called PRAME. This target has been identified and characterized by Immatics’ proprietary mass spectrometry-based discovery platform, XPRESIDENT®.

Selected PRAME which is a clean target that is prevalently and homogenously expressed across many cancers

Selected a peptide with high copy number expressed per tumor cell

Designed and engineered TCR that has optimized affinity

Manufacturing process with only 7 days ex vivo expansion resulting into younger and thus fitter T cells

PRAME is homogenously expressed and highly prevalent across several solid cancer indications which makes it a very attractive target and increases the applicability of this therapeutic approach in a wide range of solid tumors as well as a broad patient population. 

How could IMA203, if approved in the future, improve the treatment landscape for solid tumors?

Immunotherapies like CAR-T-cell therapies have fundamentally changed the therapeutic landscape to treat hematological malignancies. However, their clinical efficacy in solid tumors has been limited due to the lack of highly tumor selective targets. With our proprietary target identification platform, we can identify peptides derived from proteins expressed from within the cancer cell and to a much lower extent in normal cells, which expands the number of potential targets on solid tumors significantly. With IMA203, our engineered T cells are designed to specifically target and attack solid tumors.

With IMA203, we may offer a new therapeutic approach where a one-off treatment may lead to long-term disease control for a high fraction of infused patients at an acceptable safety profile. If successful, IMA203 treatment could be made available for many patients with advanced cancer for multiple rare and common cancers. High impact for many patients and even reach earlier treatment lines over time where it coldreplace the current standard of care (SOC).

We are clearly in the early stages of our clinical development and as you know it’s a long road to approval. We continue to evaluate IMA203 and look forward to announcing further data from the program in the future.

1. Wermke M, Tsimberidou AM, Mohamed A, et al. Safety and anti-tumor activity of TCR-engineered autologous, PRAME-directed T cells across multiple advanced solid cancers at low doses – clinical update on the ACTengine® IMA203 trial. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 959
2. Immatics reports clinical responses across multiple solid tumor types in ongoing ACTengine® IMA203 phase 1a trial targeting PRAME. News release. Immatics. November 9, 2021. https://investors.immatics.com/news-releases/news-release-details/immatics-reports-clinical-responses-across-multiple-solid-0

Cedrik Britten, MD, chief medical officer, Immatics, discussed the advantages of IMA203 over other cell therapies. 

Improving Outcomes in Solid Tumors With Personalized Cell Therapies 

“The story of immunotherapy is really interesting... years ago, no one thought that immunotherapy was going to be useful for the treatment of cancer... We thought tumors did not bring any significant immune response; there were only a few researchers doing trials with immunotherapy. But now, we are seeing that immunotherapy is the future of cancer treatment.” 

Mayo Clinic and A2 Biotherapeutics are partnering to develop mesothelin (MSLN) and carcinoembryonic antigen (CEA)-targeted Tmod chimeric antigen receptor (CAR) T-cell therapies. Preclinical data on the Tmod technology were presented at the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), November 10-14, 2021, by Julian Molina, MD, PhD, professor, oncology, Mayo Clinic.

The preclinical data demonstrated the technology’s robust protective effect on surrogate normal human cells in vitro, even in mixed-cell populations, while also yielding a robust cytotoxic effect on tumor cells in xenograft models. Also presented at SITC 2021 was the BASECAMP-1 study, which is intended to identify patients with relapsed solid tumors with human leukocyte antigen (HLA) loss of heterozygosity (LOH) as a future target for Tmod cell therapy.

 spoke with Molina to learn more about the value of immunotherapy in improving the treatment landscape of lung cancer and melanoma. He also discussed advantages of Tmod technology over CAR T-cell therapy.

The hematologist/oncologist from Mayo Clinic discussed the growing presence of CAR T-cell therapies in lung cancer and melanoma. 

Improving Cancer Survival With Immunotherapy: Julian Molina, MD, PhD 

This content originally appeared on our sister site, 

spoke with Kim A. Reiss Binder, MD, medical oncologist, assistant program director, Hematology/Oncology Fellowship Program, Abramson Cancer Center, Penn Medicine, assistant professor of medicine, Hospital of the University of Pennsylvania, about the initial results of a phase 1 trial (NCT04660929) evaluating CT-0508 in patients with HER2-overexpressing solid tumors.

CT-0508 is being evaluated in an ongoing phase 1 trial in patients with HER2-overexpressing solid tumors. The cell therapy is comprised of autologous peripheral blood monocyte–derived macrophages that are transduced with an adenoviral vector containing a HER2-directed CAR and locked into an M1 phenotype.

Initial results of 2 patients treated with CT-0508 were presented during the 2021 SITC Annual Meeting. Regarding safety, 1 patient developed grade 2 cytokine release syndrome (CRS) characterized by fever and hypotension on day 3. The toxicity was resolved on day 4 with acetaminophen (Tylenol), cefepime (Maxipime), and fluids. The other patient, as well as 1 patient who was treated on study but not included in the poster presentation, did not develop CRS with CT-0508.

Although further data are needed to determine whether this therapy is safe, patients treated with CT-0508 are unlikely to develop severe CRS based on the therapy’s mechanism of action, Reiss Binder concludes.

The oncologist from Abramson Cancer Center, Penn Medicine discussed the initial results of the phase 1 trial of CT-0508 in HER2-overexpressing solid tumors.

Initial Results of CT-0508 in HER2+ Solid Tumors: Kim A. Reiss Binder, MD

“HLA LOH is the tool that is going to allow us to discriminate normal cells from cancer cells. It's going to allow the target construct to be able to be more specific and to prevent some of those off-target effects. We're starting with HLA A2 because this is the most prevalent allele. The key issue is going to be for us to identify this group of patients that have HLA loss in the tumors because those are the candidates for future studies.”

Julian Molina, MD, PhD, professor, oncology, Mayo Clinic, and colleagues are conducting the BASECAMP-1 to identify patients with relapsed solid tumors with human leukocyte antigen (HLA) loss of heterozygosity (LOH) as a future target for mesothelin (MSLN) and carcinoembryonic antigen (CEA)-targeted Tmod chimeric antigen receptor (CAR) T-cell therapies. Molina presented the study at the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), November 10-14, 2021.

A2 Biotherapeutics is developing the Tmod CAR T-cell therapies, preclinical data on which were also presented at SITC 2021. These data demonstrated the technology’s robust protective effect on surrogate normal human cells in vitro, even in mixed-cell populations, while also yielding a robust cytotoxic effect on tumor cells in xenograft models.

 spoke with Molina to learn more about the role of HLA LOH as a useful biomarker in cancer cells. He also discussed the Tempus genomic sequencing technology being used in the study.

The hematologist/oncologist from Mayo Clinic discussed the role of HLA loss in common cancers and its use as a biomarker. 

Using HLA LOH as a Biomarker in Targeting Cancers: Julian Molina, MD, PhD 

Immatics’ IMA203, an autologous, TCR-engineered T cell (TCR-T), PRAME-directed therapy seems efficacious 

, according to data from the IMA203 phase 1 trial (NCT03686124).

Data from the trial, which has dosed 16 heavily pre-treated patients across dose levels as of August 15, 2021, were presented at the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), November 10-14, 2021, by investigator Martin Wermke, MD, University Hospital Dresden.

IMA203 seemed to be well-tolerated, with only transient and manageable treatment-emergent adverse events (AEs). In terms of efficacy, all 12 evaluable patients achieved disease control, defined as stable disease (SD) or a partial response (PR), with 6 patients demonstrated PRs according to RECIST1.1.

 spoke with Cedrik Britten, MD, chief medical officer, Immatics, to learn more about IMA203 and the data presented at SITC 2021. He also discussed the advantages of the ACTengline and ACTallo platforms used in developing the therapy.

 Can you give me an overview of the positive data presented at SITC?

 At SITC we presented the latest update from our ongoing clinical trial with IMA203, a product candidate from our ACTengine® series, which is being evaluated in advanced solid tumor patients. The trial is a Phase 1a dose escalation study and we have now analyzed data from patients treated with the first three of four dose levels. We are excited that we could show a high preliminary objective response rate at doses below 1 billion total transduced CD8 T cells, which is a dose that is below a threshold where we expected to see initial activity and below our target dose. IMA203 continues to show high levels of T cell engraftment, persistence, and tumor infiltration at these first three dose levels. For 94% of patients treated with IMA203 we achieved disease control and 88% of patients showed tumor shrinkage. Objective response rates were observed in 50% of patients across multiple solid cancer types which is very encouraging data for heavily pre-treated patients at doses below the target dose level.

Can you tell me about the ACTengine and ACTallo platforms and their advantages in creating cell therapies?

ACTengine® is a personalized approach for patients with advanced solid tumors. The patient’s own T cells are genetically engineered to express a novel, proprietary T cell receptor directed against a defined cancer target. The modified T cells are then reinfused into the patient to attack the tumor, an approach also known as TCR-T. Immatics is further advancing the adoptive cell therapy (ACT) approach beyond individualized manufacturing with its product class, ACTallo®. ACTallo® is a process to manufacture allogeneic, off-the-shelf, TCR-engineered cellular therapies derived from healthy donors’ gamma delta T cells. Using healthy donor T cells circumvents the need to use T cells from heavily pre-treated or aging cancer patients. In addition, products are available immediately for patient treatment upon enrollment without any delays for individualized manufacturing. Off-the-shelf products are readily available and thus may even reach more patients that do not have the time to wait for an autologous product. Next to the increased reach into larger patient populations, ACTallo may be supplied at much reduced cost of goods and may lend itself to repeat dosing approaches.

What are next steps/further research for IMA203?

Based on the promising preliminary results, Immatics plans to expand the IMA203 study to three study cohorts. These will include IMA203 as a monotherapy, IMA203 in combination with an immune checkpoint inhibitor and a second generation approach in which IMA203 cells are co-transduced with a CD8 co-receptor, called IMA203CD8. Each of these three cohorts could trigger further clinical development in selected tumors of special interest in separate cohorts. Selected tumors of special interest could trigger entry to late-stage clinical development with either fast path to filing or early access to significant patient populations with high unmet medical need. 

Right now, Immatics is enrolling patients to the 4th and highest dose level which means up to 2.5 billion total transduced cells for the ACTengine® IMA203 trial. We look forward to providing updates on these clinical outcomes in 2022.

Cedrik Britten, MD, chief medical officer, Immatics discussed data on IMA203 presented at SITC 2021. 

Improving Personalized Cell Therapies for Solid Tumors

"BASECAMP is limited to identifying patients that are candidates, doing the analysis, looking for HLA loss... and then harvesting those cells via leukapheresis and storing those cells until the patient has a progression. At that time... a board of several of us will discuss if the patient is going to be a good candidate or not.”

BASECAMP-1 is identifying patients with relapsed solid tumors with human leukocyte antigen (HLA) loss of heterozygosity (LOH) as a future target for mesothelin (MSLN) and carcinoembryonic antigen (CEA)-targeted Tmod chimeric antigen receptor (CAR) T-cell therapies. The study was presented at the 

A2 Biotherapeutics also announced preclinical data on the Tmod system at SITC 2021 that demonstrated its robust protective effect on surrogate normal human cells in vitro, even in mixed-cell populations, while also yielding a robust cytotoxic effect on tumor cells in xenograft models.

 spoke with Molina to learn more about the BASECAMP-1 study and how it will inform and increase efficiency in future trials assessing Tmod technology.

The hematologist/oncologist from Mayo Clinic discussed the BASECAMP study and how it will inform future studies assessing Tmod technology. 

Identifying Future Patients for Tmod Cell Therapy in BASECAMP-1: Julian Molina, MD, PhD 

CRISPR Therapeutics presented positive preclinical data on their chimeric antigen receptor (CAR) programs at the 

36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC)

Data on the company’s CRISPR/Cas9 gene-edited, allogeneic, CD33-targeted CAR-T cell program in acute myeloid leukemia (AML) were presented by Jonathan Terrett, PhD, head, Immuno-Oncology Research and Translation, CRISPR Therapeutics.

“We have shown previously that allogeneic CRISPR/Cas9 gene-edited CAR-T cells targeting CD33 with TRAC disruption to reduce GvHD and B2M disruption to reduce allogeneic host rejection could eliminate tumors in xenograft models of AM,” Terrett and colleagues wrote.

 “Given that off-target activity of the toxin could contribute to the myeloablation seen with CD33-targeted ADCs, we created in vitro and in vivo models to examine reconstitution of the myeloid compartment following treatment of CD33-targeted allogeneic CAR-T cells.”

The gene-edited CAR T-cell therapy showed efficacy in CD33+ tumor cells while CD34+ cells expanded and differentiated. In mice, the THP-1 AML tumor was eradicated without long-term myelosuppression or B cell aplasia. Terrett and colleagues concluded that the edited CAR T-cell therapy may be both efficacious and tolerable in AML.

Gene Therapies for ALS, Friedreich’s Ataxia the Focus of New CRISPR, Capsida Partnership

Data on the CRISPR/Cas9 gene-edited, CISH gene-knockout, CD70-targeted CAR natural killer (NK) cell therapy program in a variety of cancers were presented jointly by CRISPR and Nkarta Therapeutics by Chao Guo, PhD, principal scientist, Nkarta.

“Here we show the potential application of CISH gene-knockout CAR NK cells targeting CD70 and expressing a membrane-bound form of IL-15. CD70 is an antigen that is aberrantly expressed in a variety of malignant settings, including renal cell carcinoma (RCC), while its expression in normal tissues is restricted to a subset of lymphoid cell types,” Guo and colleagues wrote.

Guo and colleagues generated CD70-targeted CAR NK cells and knocked-out the CISH gene by CRISPR/Cas9 editing. They expanded the cells and transduced them to express the targeted CAR and mbIL-15. They then assessed CAR expression, NK cell persistence, and NK cell activity against RCC target cells using end-point cytotoxicity assays and IncuCyte.

The researchers found that the engineered CAR NK cells could be produced efficiently and persisted in prolonged culture, maintaining their activity. The CD70-CAR transduction efficiency was 60–80% after transduction and expansion. The CAR NK cells exhibited potent cytotoxicity against CD70+ RCC cell lines. They also found that the engineered cells were partially resistant to TGFß and adenosine inhibition of cytotoxicity via cytotoxicity assays.

"In summary, we show CISH gene-knockout CD70-CAR NK cells demonstrate potent anti-tumor activity against relevant solid tumor cell lines and partially provide resistance to tumor microenvironment inhibition. These data support the further exploration of CISH gene-knockout CD70 CAR NK cells for clinical application,” Guo and colleagues concluded.

Another of CRIPSR’s programs, CTX110, recently showed 

 in the phase 1 CARBON trial (NCT04035434) in patients with relapsed or refractory CD19+ B-cell malignancies.

 A single infusion of the allogeneic CAR T-cell therapy at dose level 2 (100x106 cells) and above yielded an overall response rate (ORR) of 58% and a complete response (CR) rate of 38% in patients with large B-cell lymphoma (LBCL). These responses were durable, with a 6-month CR rate of 21% and the longest response ongoing at over 18 months post-treatment.

“CTX110 could offer patients with large B-cell lymphomas an immediately available ‘off-the-shelf’ therapy with efficacy similar to autologous CAR-T and a differentiated safety profile,” said Samarth Kulkarni, PhD, chief executive officer, CRISPR Therapeutics, in a statement.

1. CRISPR Therapeutics to Present Preclinical Data at the Society for Immunotherapy of Cancer (SITC) 36th Annual Meeting. News release. CRISPR Therapeutics. October 1, 2021. 

https://www.globenewswire.com/news-release/2021/10/01/2307003/0/en/CRISPR-Therapeutics-to-Present-Preclinical-Data-at-the-Society-for-Immunotherapy-of-Cancer-SITC-36th-Annual-Meeting.html


2. Terrett J, Mcewan B, Hostetter D, et al. CRISPR/Cas9 gene-edited allogeneic CAR-T cells targeting CD33 show high preclinical efficacy against AML without long-term hematopoietic toxicity. Presented at: Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 133
3. Guo C, Fan Y, Aronov A, et al. CISH gene-knockout anti-CD70-CAR NK cells demonstrate potent anti-tumor activity against solid tumor cell lines and provide partial resistance to tumor microenvironment inhibition. Presented at: Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 113
4. CRISPR Therapeutics reports positive results from its phase 1 CARBON Trial of CTX110™ in relapsed or refractory CD19+ B-cell malignancies. News release. CRISPR Therapeutics. October 12, 2021. https://crisprtx.gcs-web.com/news-releases/news-release-details/crispr-therapeutics-reports-positive-results-its-phase-1-carbon

CRISPR Therapeutics presented positive data on 2 preclinical programs at the 2021 SITC meeting. 

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