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Society for Immunotherapy of Cancer (SITC)

“Cellular therapy for metastatic melanoma has been a relatively niche field until recently. This reminds me of the implementation of solid organ transplant. At the onset of this type of complex therapy, the therapy was initially implemented at select centers of excellence. But as the therapy gets developed more and practitioners learn more about this exciting technology, I think the technology will be moved to more and more centers in the future. However, this will require some institutional investment in infrastructure...”

Cell therapy is an emerging area of interest for the treatment of patients with advanced melanoma. Iovance Biotherapeutics’ lifileucel (LN-144), an investigational autologous tumor infiltrating lymphocyte (TIL) therapy, is currently being investigated as a potential new treatment option for these patients.

, MD, FACS, Moffitt Cancer Center and University of South Florida, 

 from the phase 2 C-144-01 (NCT02360579) clinical trial evaluating lifileucel at 

the Society for Immunotherapy of Cancer’s (SITC)

 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts.

, Sarnaik discussed several areas of interest in cell therapy research on the horizon for advanced melanoma. He specifically mentioned investigations into CRISPR/Cas9 genetic manipulation of cellular products, which is already underway. Sarnaik also spoke about biomarker development as an area of unmet need for advanced melanoma patients that could be addressed with the help of patient-derived materials obtained during treatment with lifileucel or other cell therapies. He also briefly discussed combination therapy, another area of ongoing research.

Sarnaik discussed several potential areas of innovation on the horizon. 

Amod Sarnaik, MD, on New Frontiers in Cell Therapy for Advanced Melanoma 

“When the pandemic began, we all felt pretty helpless. We had really no viable therapies to treat our patients. The ones that were getting intensely ill were requiring mechanical ventilation and even more sophisticated therapies like lung bypass and extracorporeal membrane oxygenation [ECMO], and were all dying at a pretty high rate. I think our survival rate initially was maybe 10 or 20%, when people got sick enough to be placed on mechanical support... I think all of us were searching for options and how to improve the outcomes in these tremendously ill patients.”

The allogeneic off-the-shelf invariant natural killer T-cell (iNKT) therapy, agenT-797 (MiNK Therapeutics), was well-tolerated and improved survival in patients with COVID-19-associated acute respiratory distress syndrome (ARDS) in addition to mechanical ventilation or ECMO.

These findings, from a phase 1/2 trial (NCT04582201) were presented at the 

Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting

, November 8-12, 2022, in Boston, Massachusetts, by Terese Hammond, MD, pulmonologist and medical director, cardiac care unit/intensive care unit, Saint John’s Health Center.

spoke with Hammond to learn more about the need for more treatment options in patients with COVID-associated ARDS. She discussed the advantages of iNKT cells to bolster the immune system in more traditional cell therapy applications in oncology as well as respiratory indications like ARDS.

Click here to view more coverage of the 2022 SITC Annual Meeting.

Purbhoo MA, Yigit B, Moskowitz D, et al. Invariant natural killer T (iNKT) cell therapy (agenT-797) in subjects with moderate to severe acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 (COVID-19). Presented at: SITC 37th Annual Meetin,g November 8-12, 2022, in Boston, Massachusetts. Poster #649

The director of the CCU/ICU at Saint John’s Health Center discussed unmet respiratory treatment needs in the beginning of the COVID-19 pandemic. 

Terese Hammond, MD, on Investigating iNKT Cells in COVID-Associated ARDS 

“There are definitely challenges associated with implementation of a product as complex as lifileucel. This requires mobilization of resources that as a medical field we're not quite used to. The treatment does involve extensive patient and caregiver education, as well as mobilization of resources associated with practitioners of surgical oncology, medical oncology, as well as cellular therapy. Of note, cellular therapy is still a relatively emerging field, and therefore represents a relatively scarce resource.”

While there are various treatments available for patients with advanced melanoma, many of these treatments have substantial limitations or drawbacks, leaving some patients with few viable options. In this situation, some patients will turn to investigational therapies being evaluated in clinical trials.

Amod A. Sarnaik, MD, FACS, Moffitt Cancer Center and University of South Florida, 

 from the phase 2 C-144-01 (NCT02360579) clinical trial evaluating lifileucel (LN-144), an investigational autologous tumor infiltrating lymphocyte (TIL) therapy, at 

, Sarnaik discussed the current treatment landscape for advanced melanoma, going over the various options available and their respective limitations, and then gave his view on where lifileucel could fit into this landscape if it becomes an approved therapy. He also discussed some of the challenges of implementing lifileucel in the clinic, going over the infrastructural limitations that currently make cell therapy options less accessible for patients than more conventional treatments.

Sarnaik discussed the investigational TIL therapy’s potential as an additional option for patients. 

Amod Sarnaik, MD, on Lifileucel’s Place in the Treatment Lanscape for Advanced Melanoma 

Combination treatment of CAN-2409 plus valacyclovir plus nivolumab and standard of care seems to improve survival in patients with newly diagnosed, high-grade glioma intended for gross total resection (GTR).

These data, from 35 evaluable participants in a phase 1 study (NCT03576612), were presented in a late-breaking oral abstract at the 

Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting

, November 8-12, 2022, in Boston, Massachusetts, by Patrick Wen, MD, professor, neurology, Harvard Medical School, and director, Center for Neuro-Oncology, Dana-Farber Cancer Institute.

“The development of effective immunotherapy forbrain tumors has been limited by the suppressed tumor microenvironment. There is a paucity of T-cell infiltration in these tumors and enhancement of immunosuppressive macrophages and microglia. These tumors make immunosuppressive factors like IL10 and TGFβ. The majority of these patients undergo radiotherapy and temozolomide chemotherapy, producing a profound and long-lasting lymphopenia, and most of these patients are also on corticosteroids,” Wen said during his presentation.1

The phase 1 trial was launched in a collaboration with the Adult Brain Tumor Consortium, Bristol-Myers Squibb, and Candel Therapeutics.Forty-oneparticipants were enrolled to receive an injection of 2.5x1011 vp of CAN-2409 during resection surgery, followed by temozolomide and nivolumab after around 2 and 3 weeks, respectively.Participants had a median age of 62 years, all but 1 had glioblastoma, and 73% of patients actually achieved a GTR.

IL13Rα2 Universal CAR T Therapy Shows Antitumor Activity in Recurrent Glioma

Around 2/3 of participants were found to have unmethylated MGMT promoters and temozolomide was discontinued while the 1/3 with methylated MGMT promoters continued temozolomide treatment, first with radiation and then with nivolumab. The study’s primary endpoint was safety while secondary endpoints included overall survival (OS), progression free survival, radiologic changes, and immunological biomarkers.

The treatment regimen was generally well-tolerated and consistent with standard-of-care resection, with no dose-limiting toxicities. The most common adverse events (AEs) included fatigue (n = 16; 39%), nausea (n = 12; 29%), and alanine transaminase elevations (n = 10; 24%). More serious, grade 3-4 AEs included neutrophil decreases, acute kidney injury, and hypertension (n = 2 each; 5%). Nine participants discontinued the study based off AEs associated with temozolomide and nivolumab treatments, underlying disease symptoms, or unrelated medical events.

Overall, study participants had an OS of 15.1 months. Patients with methylated MGMT promoters who achieved GTR had a median OS of 30.6 months (n = 10) while those who did not achieve a GTR had a median OS of 12.6 months (n = 5). Patients with unmethylated MGMT promoters who achieved GTR had a median OS of 13.2 months (n = 16) while those who did not achieve GTR had a median OS of 15.9 months (n = 4).

Immune profiling performed in collaboration with CIMAC-CIDC revealed that CAN-2409 elicited a strong systemic activation of effector immune response, and, in combination with nivolumab, expanded activated CD4/CD8 T cells and decreased exhaustion.

“We are encouraged to see strong systemic immune activation after a single administration of CAN-2409 to the resection bed during neurosurgical removal of the tumor combined with nivolumab treatment in one of the most treatment-resistant cancers, high-grade glioma, which is characterized by a highly immunosuppressive microenvironment,” Paul Peter Tak, MD, PhD, FMedSci, president and chief executive officer, Candel Therapeutics, said in a statement.

“The data support the potential therapeutic synergies between CAN-2409 in combination with immune checkpoint inhibitors across various solid tumors.”

Click here to view more coverage of the STIC 2022 Annual Meeting.

1. Wen P. First efficacy and multi-omic analysis data from phase 1 clinical trial of oncolytic viral immunotherapy with CAN-2409 + valacyclovir in combination with nivolumab and standard of care in newly diagnosed high-grade glioma. Presented at: SITC 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts.
2. Candel Therapeutics announces late-breaking oral presentation at SITC Annual Meeting with data on CAN-2409 in combination with nivolumab in a phase 1 mechanistic clinical trial in patients with high-grade glioma. News release. Candel Therapeutics. November 11, 2022. https://ir.candeltx.com/news-releases/news-release-details/candel-therapeutics-announces-late-breaking-oral-presentation

CAN-2409 transduces tumor cells with the thymidine kinase gene, sensitizes these cells to valacyclovir, and stimulates patients’ immune response. 

Combination Adenovirus Therapy Shows Survival Gains in Newly Diagnosed High-Grade Glioma 

(CAR-M) therapy demonstrated safety, feasibility, and clinical validation of its mechanism of action in HER2-overexpressing solid tumors in updated data from a phase 1, first-in-human study (NCT04660929).

 Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting

, November 8-12, 2022, in Boston, Massachusetts, by Kim A. Reiss Binder, MD, assistant professor of medicine, University of Pennsylvania Hospital.1

“In preclinical studies, CAR-M phagocytose tumor cells, activate the tumor microenvironment (TME), recruit T cells, and induce antitumor T cell immunity. CT-0508 is a first-in-class CAR-M, comprised of autologous monocyte derived macrophages expressing an anti-HER2 CAR,” Reiss said during her presentation.

The trial has dosed 9 participants with breast (n = 4), esophageal (n = 2), choloangiocarcinoma (n = 1), ovarian (n = 1), and salivary carcinoma (n = 1) cancer. Participants had a median age of 58 years (range, 45-73); 3 (33.3%) were male, and all were White. Participants had a median of 3 prior therapies (range, 2-11) and a median of 2 prior anti-HER2 therapies (range, 0-9). Five participants (55.6%) had also received prior radiotherapy.

Kim A. Reiss Binder, MD, on the Potential of CAR Macrophages in Solid Tumors

Reiss and colleagues found that CT-0508 was well-tolerated with no dose-limiting toxicities or major organ toxicities. Most adverse events (AEs) were grade 1 or 2, although there were 5 serious AEs that did occur. These included 2 cases of cytokine release syndrome and 1 infusion reaction deemed related to treatment as well as 1 case of gastrointestinal hemorrhage and 1 case of worsening dyspnea related to progressive disease. No AEs led to study discontinuation or CT-0508 dose modification. The investigators also explored preliminary efficacy and determined a best overall response of stable disease in 5 participants (55.6%).

“The data from Group 1 of our first-in-human CAR-M clinical trial provides evidence that CAR-M therapy is feasible and generally well-tolerated by patients with certain late-stage metastatic cancers,” Michael Klichinsky, PharmD, PhD, cofounder and chief scientific officer, Carisma Therapeutics, said in a statement.

 “The translational data collected from these patients is highly encouraging. We look forward to advancing CT-0508 into Group 2 of the monotherapy safety trial, as well as in a combination sub-study with the T cell checkpoint inhibitor pembrolizumab.”

Biomarker studies were also conducted and revealed transient elevations of pro-inflammatory cytokines, which resolved within 48 hours.

 RNAscope technology confirmed rapid migration out of the blood within 4 to 8 hours and into the TME in 8 participants. Biopsies revealed activation of the TME in 6 participants as well as increased T cell clonality. These clones were found to be cytotoxic within the TME.

“CT-0508 led to increased T-cell clonality and significant expansion of newly emergent T cell clones within the TME with concomitant CD8 T cell activation, demonstrating induction of anti-tumor immunity,” Reiss concluded her presentation.

Click here to view more coverage of the 2022 SITC meeting.

1. Reiss KA, Yuan Y, Ueno NT, et al. A phase 1, first-in-human (FIH) clinical trial of the anti-HER2 CAR macrophage CT-0508 in participants with HER2 overexpressing solid tumors.Presented at: SITC 37th Annual Meeting, November 8012, 2022, in Boston, Massachusetts. Poster #634
2. Carisma Therapeutics announces clinical & pre-clinical updates. News release. Carisma Therapeutics. November 11, 2022. https://carismatx.com/carisma-therapeutics-announces-clinical-pre-clinical-updates/

Updated data from a first-in-human trial were presented at the SITC 2022 meeting. 

CT-0508 Demonstrates Cytotoxicity in Solid Tumors 

Affini-T Therapeutics’ AFNT-111, an investigational T-cell receptor (TCR)-engineered therapy that targets 

 G12V-expressing tumor cells with the intention of treating patients with solid tumors, has demonstrated promising potency and specificity in preclinical studies.

Society for Immunotherapy of Cancer’s (SITC)

 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts, by Hubert Lam, PhD, vice president of Preclinical Development, Affini-T Therapeutics.

AFNT-111 is comprised of autologous CD4+ and CD8+ T-cells that have been transduced to express both a TCR with high affinity for 

 G12V mutations, which account for approximately 30% of 

 mutations, and a CD8α/β co-receptor which allows for MHC 1 target recognition and induces a CD4+/CD8+ T-cell response which helps to prevent exhaustion and enable T-cell persistence. AFNT-111 utilizes a TCR candidate that has been identified from healthy donor TCRs with a discovery platform developed in collaboration with Fred Hutch Cancer Research Center. The TCRs identified by the platform are high-affinity and have cleared thymic selection for self-reactivity. The AFNT-111 TCR was additionally verified to be able to recognize endogenous 

 G12V presented by cell lines derived from various cancer types including pancreatic, colon, lung, breast, and ovarian.

“At Affinity Therapeutics we believe that a key vulnerability of cancer are these oncogenic driver mutations,” Lam said during his presentation. “Since they're responsible for the cancer itself, they're truncal, ubiquitously expressed throughout the tumor. So, if you can kill the cancer cells that have them, you can limit tumor escape and address the whole tumor. In addition, since these are mutated proteins unique to cancer they can be recognized as foreign by the immune system, limiting the safety concerns associated with targeting non-mutated self-antigens. 

 is the most frequent of these oncogenic drivers in solid tumors, present in an enormous number of human cancers including pancreatic, colorectal, and lung.”

In vitro data showed that AFNT-111 cells had increased ability to control and kill recognized tumor cells compared to untransduced (UTD) controls in several of these cell lines. This ability remained in the face of rechallenges with additional tumor cells, indicating AFNT-111 cells’ potential for persistence. Increased anti-tumor activity of AFNT-111 compared to UTD controls was also seen in immunodeficient NOD scid gamma (NSG) mouse models of breast cancer, pancreatic cancer, and colon cancer. In terms of safety, an in-silico assessment across the human proteome based on XScan assay results indicated 22 peptides of potential concern. However, of these, the study did not identify any cross-reactive self-peptides of concern.

“These 22 peptides were tested with no cross-reactivity identified,” Lam explained during his presentation. “RAB7B was a peptide that had weak potential cross-reactivity; this was further tested, and it had a 400,000-fold lower EC50 as compared to G12V, showing non-biological-relevance at an EC50 of 35 micromolar. We also tested alloreactive responses with no alloreactivity identified in a large B-LCL library, with also no cytokine-independent growth seen with this cell therapy.”

Affini-T Therapeutics is planning to submit an investigational new drug application for AFNT-111 in the first half of next year. The company plans to carry out a phase 1 clinical trial for the therapy along with Fred Hutch Cancer Research Center. The trial will evaluate safety, tolerability, and preliminary efficacy, and aim to determine the maximum tolerated dose. It will include patients with advanced or metastatic pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, or non-small cell lung cancer who are 

Hubert L. AFNT-111, a safe and effective TCR-engineered T cell therapy targeting the oncogenic driver KRAS G12V mutation. Presented at: Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting November 8-12, 2022; Boston, Massachusetts. Abstract #244

AFNT-111 showed anti-tumor activity in NSG mouse models of breast cancer, pancreatic cancer, and colon cancer. 

KRAS-Directed TCR Therapy Shows Promising Preclinical Efficacy and Safety 

"Lifileucel is a 1-time therapy. The toxicity is manageable and usually related to the preconditioning or the IL2. So, what you have is the ability to give a viable option to our patients that is a1-time option and can give durability of response.”

The investigational autologous tumor infiltrating lymphocyte (TIL) therapy lifileucel (Iovance Biotherapeutics) has demonstrated encouraging efficacy and a manageable safety profile in pooled data from 2 cohorts of patients with heavily pretreated advanced melanoma in the phase 2 C-144-01 (NCT02360579) clinical trial. Data from the study were presented at the 

, November 8-12, 2022, in Boston, Massachusetts, by Amod A. Sarnaik, MD, FACS, Moffitt Cancer Center.

Investigators found that lifileucel had an objective response rate of 31.4% in the 2 cohorts, with 9 complete responses and 39 partial responses. Median duration of response(DOR) was not reached at a median follow up of 36.5 months, and 41.7% of responding patients had a DOR of 24 months or more. Median overall survival (OS) was 13.9 months, and the 12-month OS rate was 54% (95% CI: 45.6%, 61.6%)

 spoke with the study's co-author Omid Hamid, MD, chief, research and immunotherapy, Cedars-Sinai - The Angeles Clinic and Research Institute, to learn more about the C-144-01 study and the lifileucel TIL therapy. He discussed the advantages of the therapy in melanoma and how the research forwards progress for immunotherapy in solid tumors as a whole.

Click here to read more coverage of SITC 2022.

Sarnaik A. Lifileucel TIL cell monotherapy in patients with advanced melanoma after progression on immune checkpoint inhibitors (ICI) and targeted therapy: Pooled analysis of consecutive cohorts (C-144-01 study). Presented at: Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting November 8-12, 2022; Boston, Massachusetts. Abstract #789

The chief of research and immunotherapy at Cedars-Sinai The Angeles Clinic and Research Institute discussed updated data from the phase 2 C-144-01 study of the lifileucel TIL therapy. 

Omid Hamid, MD, on Improving Duration of Response in Refractory Melanoma With Lifileucel 

, the carcinoembryonic antigen (CEA)-targeted A2B530 and the mesothelin (MSLN)-targeted A2B694, have demonstrated proof-of-concept in their abilities to target tumor cells in preclinical studies.

These data were presented at the Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts. J. Randolph Hect, MD, professor, clinical medicine, David Geffen School of Medicine, University of California – Los Angeles (UCLA), and director, UCLA Gastrointestinal Oncology Program, gave the presentation on A2B530. Julian R. Molina, MD, PhD, oncologist, Mayo Clinic, gave the presentation on A2B694.

“Nearly all colorectal and more pancreatic and lung cancers express CEA. However, due to its expression in normal gut epithelial cells, CEA-targeted therapies have resulted in on-target, off-tumor toxicity. To overcome this, we have developed Tmod, a logic-gated T-cell therapy platform. Tmod constructs are composed of an activating chimeric antigen receptor (CAR) or T-cell receptor that targets a tumor antigen and an inhibitory receptor recognizing an antigen expressed on normal healthy tissues, but not on tumor cells due to loss of heterozygosity (LOH),” Hecht said during his presentation.

Both cell products are developed using T cells from HLA-A*02+ donors transduced with a lentivirus construct to express the CAR, the blocker, and a short-hairpin RNA targeting β2M. Cytotoxicity was measured in cultured cell lines that were CEA or MSLN+with LOH and no LOH. Mice were also treated intravenously with CEA/MSLN CAR Tmod cells or control T cells.

Breanna DiAndreth, PhD, on Improving Selective Targeting of Tumor Cells

“A2B530 is an autologous CEA Tmod cell product that exploits common loss of heterozygosity at the HLA locus in cancer cells, enabling these engineered T cells to distinguish between normal and tumor cells,” Molina said during his presentation.

Both A2B530 and A2B694 exhibited on-target, off-tumor selectivity in vitro, as well as selective killing of tumor cells when mixed in culture with normal cells, with minimal off-target effects in vitro. This selective killing was also seen in vivo in mice models.

“BASECAMP-1 [NCT04981119], an observational study that will identify patients with somatic HLA LOH, is currently recruiting. Eligible patients with metastatic colorectal, pancreatic, ovarian, mesothelioma or non-small cell lung cancer will be apheresed for a future interventional study (EVEREST-2) [with A2B694],” Molina concluded his presentation.

Similarly, A2B530 will be evaluated in the future EVEREST-1 interventional study.

Another poster presented at the SITC meeting gave updates on the BASECAMP-1 trial, which has enrolled 4 participants so far. The trial is enrolling in sites across the US.

“The unmet medical need in lung, colorectal and particularly pancreatic cancer remains extremely high. BASECAMP-1 is a non-interventional pre-screening trial that identifies eligible patients and banks their T cells. If the patients have the misfortune to relapse or progress, A2 Bio will have their cells ready to be manufactured and dosed in our upcoming Phase 1 studies targeting CEA and MSLN,” William Go, MD, PhD, chief medical officer, A2 Bio, said in a statement.

1. Mardiros A, Patel S, Kamb A, et al. A2B530, an autologous CEA-directed Tmod T-cell therapy with an inhibitory receptor gated by HLA-A*02 to target colorectal, pancreatic, and lung cancer. Presented at: SITC 37th Annual Meeting, November 8-12, 2022, Boston, Massachusetts. Abstract #229.
2. Patel S, Kamb A, Morelli MP, et al. A2B694, an autologous logic-gated cell therapy targeting mesothelin. Presented at: SITC 37th Annual Meeting, November 8-12, 2022, Boston, Massachusetts. Abstract #263.
3. A2 Bio identifying solid tumor patients for possible inclusion in phase 1 studies targeting CEA and mesothelin expected to begin in 2023: Update at SITC 2022. News release. A2 Bio. November 7, 2022. https://www.businesswire.com/news/home/20221107005336/en/A2-Bio-Identifying-Solid-Tumor-Patients-for-Possible-Inclusion-in-Phase-1-Studies-Targeting-CEA-and-Mesothelin-Expected-to-Begin-in-2023-Update-at-SITC-2022

A2B530 and A2B694 target CEA and MSLN cells that have HLA loss of heterozygosity. 

HLA LOH-Targeting Tmod Cell Therapies Demonstrate Selective Killing of Tumor Cells in Mice  

PACT Pharma’s NeoTCR-P1, an investigational personalized adoptive T-cell Receptor (TCR) therapy that is intended to target neo-antigens specific to patients’ own tumors, showed promising safety and proof-of-concept in patients with solid tumors in data from a phase 1a/b clinical trial (NCT03970382) presented at the 

NeoTCR-P1 consists of autologous cells with 

 that recognize patient-specific neoantigens. Non-viral precision gene editing is used to knock out endogenous TCRs and knock-in the best patient-specific neoTCRs, which are selected with a proprietary algorithm. Proof-of-concept of the screening and manufacturing process was demonstrated in the trial, and the cell product additionally showed ability to travel to tumors after infusion into patients. Among the 16 patients treated in the trial, 5 showed stable disease after treatment.

"Our algorithm takes into account the activation status of the T-cell that we isolated the TCR from, the TCR functionality, of course, and the neo-epitope truncality and expression, and also HLA diversity,” Stefanie Mandl, PhD, chief scientific officer, PACT Pharma, explained during her presentation. “We've developed a completely non-viral precision genome engineering process for the engineering of our neo-TCR T-cells. This is a single step process, and we're using CRISPR editing to simultaneously knock-out the endogenous TCR and then knock-in the neo-TCR. And in that way, we generate a T-cell in which the neo-TCR is expressed from the endogenous promoter and regulated and expressed at normal levels.”

In terms of safety, the treatment was well-tolerated, with the majority of adverse events (AEs) being attributed to the conditioning chemotherapy regimen. Excepting a single patient who experienced a grade 1 case of cytokine release syndrome (CRS), there were no incidences of CRS among the treated patients. A grade 3 case of encephalopathy was experienced by a patient with non-small cell lung-cancer (NSCLC) who had existing and worsening brain metastasis, but resolved after steroid treatment. Other AEs greater than grade 3 that occurred in the treated patients included anemia, febrile neutropenia, pancytopenia, thrombocytopenia, lymphopenia, neutropenia, leukopenia, and herpes zoster infection. All 16 patients cleared the full dose-limiting toxicity window.

In total 187 patients signed informed consent for the trial, 88 patients were screened for TCRs, and 16 were dosed. Four of the 16 patients received NeoTCR-P1 along with IL-2, while the remaining 12 received NeoTCR-P1 alone. The ages of the patients who received treatment ranged from 35 to 69 (median, 47), and there were 10 male patients and 6 female patients included. Cancer types of the patients treated included microsatellite stable (MSS)-colorectal cancer (n=11), HR+ breast cancer (n=2), ovarian cancer (n=1), melanoma (n=1), and NSCLC (n=1). The patients had previously been treated with between 2 and 9 prior regimens of therapy (median, 5). End points for the trial included the feasibility of TCR discovery and manufacturing of a multi-TCR product using complete non-viral gene editing and the incidents and nature of AEs defined as DLTs. Secondary end points included the overall response rate, duration of response, progression-free survival, and overall survival. In addition, retrospective benchmarking comparing the TCRs in the study to TCRs used in other studies was conducted.

“The retrospective benchmarking to other TCRs that showed clinical signal was very important...,” Mandl added in response to an audience question about potential drivers for better responses. “We have in the beginning cast a very wide net for TCR potencies because there are data in the literature that show that the high affinity TCRs are exhausting faster, and then in chronic infection, for example, lower affinity TCRs become more dominant. This is not what we saw in our study. And we could do the perfect experiment where we had 3 different T-cells with different affinities in the same patient. And I can tell you, I would now go with higher affinity TCRs.”

Mandl S. 1478 A phase I study of personalized adoptive TCR T cell therapy in patients with solid tumors: safety, efficacy, and T cell trafficking to tumors of non-virally gene edited T cells. Presented at: Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting November 8-12, 2022; Boston, Massachusetts.

Among the 16 patients treated in the trial, 5 showed stable disease after treatment. 

Personalized TCR Therapy Safe, Feasible in First-in-Human Trial 

CTX130 was well-tolerated and yielded a complete response (CR) in relapsed or refractory renal cell carcinoma (RCC).

These data, from the first-in-human phase 1 COBALT-RCC clinical trial (NCT04438083), were presented at the 

, November 8-12, 2022, in Boston, Massachusetts, by Sumanta Pal, MD, professor, department of medical oncology and therapeutics research and codirector, Kidney Cancer Program, and medical oncologist, City of Hope.

“We are very pleased by the encouraging data from our first-in-human clinical trial exploring CD70-targeting CAR-T cell therapy in clear cell RCC. In this trial, treatment with CTX130 resulted in a durable complete response, and the trial demonstrated a favorable disease control rate overall. We remain excited by the results presented today for the CTX130 trial for the treatment of relapsed or refractory RCC,” Phuong Khanh Morrow, MD, FACP, chief medical officer, CRISPR Therapeutics, said in a statement.

“Additionally, we presented a poster highlighting preclinical data that demonstrates that CRISPR-edited allogenic anti-CD83 CAR-T cells show potent activity in models of AML and can be a promising CAR-T target for the treatment of AML.”

CTX130 is an allogeneic, CRISPR/Cas9 gene-edited, CD70-targeted, chimeric antigen receptor (CAR) T-cell therapy developed by CRISPR Therapeutics and being investigated at City of Hope, among other clinical trial sites. The therapy is made using an adeno-associated virus vector to insert an anti-CD70 CAR cassette into the TRAC locus. It is designed to disrupt TRAC, β2M, and CD70.

Allogeneic CAR T Recognized for Cutaneous T-Cell Lymphomas

COBALT-RCC enrolled 14 patients with RCC with clear cell differentiation,prior exposure to checkpoint and vascular endothelial growth factor inhibitors, and adequate Karnofsky performance status and organ functions. Part a (dose escalation) primarily evaluated incidence of adverse events (AEs) and dose-limiting toxicities and part b (cohort expansion) primarily evaluated the objective response rate (ORR). Secondary endpoints evaluated best overall response, progression-free survival, and overall survival. Participants were treated with either 3x10

 cells. Patients’ tumors had a median CD70 expression of 100% (range, 1-100) and a mean of over 75%.

“At present, a treatment that offers patients with advanced kidney cancer the possibility of a durable remission with limited toxicity remains elusive. Our data shared today show encouraging activity for an allogeneic CAR-T therapy in this setting and highlights the potential of this modality for these patients,” Pal added to the statement.

Investigators found that half of patients had grade 1 or 2 cytokine release syndrome (CRS) but no patients had more severe CRS. Three patients had CRS counted as a serious AE related to CTX130. The median time to CRS onset was 1 day and median duration was 2 days. There were no cases of immune effector cell-associated neurotoxicity syndrome or graft-versus-host disease. Three patients had serious AEs of infections unrelated to treatment (grade 5 pneumonia and grade 4 dyspnea resulting in death). There were no incidences of tumor lysis syndrome, secondary malignancies, infusion reactions, or hemophagocytic lymphohistiocystosis, and altogether, the therapy had an acceptable safety profile.

Investigators assessed efficacy and found that 1 participant in dose level 1 (DL1) had a partial response that deepened to a CR in 3 months, which has been maintained as of 18 months post-infusion. Nine patients (2 in DL1, 2 in DL2, 2 in DL3, and 3 in DL4) had stable disease (SD); 4 patients still had SD at 4 months. There was an overall disease control rate of 77%.

“These encouraging results really underscore the potential of further increasing potency...To our knowledge, the durable complete response is the first to be achieved with allogeneic CAR T-cell therapy in patients with relapsed/refractory solid tumors,” Pal said during his presentation.

CTX131, a version of the therapy with second-generation edits, is currently being developed and will disrupt regnase-1 and TGFβR2. The disruption of this combination of targets was shown to increase potency by at least 10 times in preclinical studies. CRIPSR is planning clinical studies for 2023.

1. Pal S. CTX130 allogeneic CRISPR-Cas9–engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcinoma: Results from the Phase 1 COBALT-RCC study. Presented at: SITC 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts. 
2. CRISPR Therapeutics presents data at the Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting. News release. CRISPR Therapeutics. November 10, 2022. http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-presents-data-society-immunotherapy-cancer

Data from the COBALT-RCC study in renal cell carcinoma were presented at SITC 2022. 

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