A2B101-101: Obtaining Solid Tumor Tissue from Subjects Having Surgical Resection for Certain Tumor Types and Leukapheresis for CAR T-cell Therapy Manufacturing

Overview

About this study

The primary objectives for this study are:

The percentage of subjects who can enroll on an A2 CAR T-cell therapy study within approximately 6 months of documentation of HLA-A LOH status
The percentage of subjects who can enroll on an A2 CAR T-cell therapy study within approximately 12 months of documentation of HLA-A LOH status
The percentage of subjects who can enroll on an A2 CAR T-cell therapy study within approximately 18 months of documentation of HLA-A LOH status
The percentage of subjects who can enroll on an A2 CAR T-cell therapy study within approximately 24 months of HLA-A LOH status
Percentage of screened subjects experiencing loss of heterozygosity of HLA-A*02.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Key Eligibility Criteria (additional criteria may apply) Part 1 Key Inclusion Criteria

1. Pathologically confirmed solid tumors, e.g., Colorectal Cancer (CRC), Non-Small Cell
Lung Cancer (NSCLC), or Pancreatic Cancer (PANC), that is metastatic, unresectable locally
advanced, or in the Investigator's opinion the subject is high risk for incurable relapse
within two years.

Part 1: Key Exclusion Criteria

1. History of any of other malignancy in the past 5 years other than non-melanoma skin
carcinoma, low grade localized prostate cancer, superficial bladder cancer, ductal
carcinoma in situ (CIS) of the breast, CIS of the Cervix, or Stage I uterine cancer.

2. Prior allogeneic stem cell transplant.

3. Prior solid organ transplant.

Part 2 : Key Inclusion Criteria

1. Pathologically confirmed solid tumors, e.g., Colorectal Cancer (CRC), Non-Small Cell
Lung Cancer (NSCLC), Pancreatic Cancer (PANC), Mesothelioma, or Ovarian Cancer (OVAC)
that is metastatic, unresectable locally advanced, or in the Investigator's opinion
the subject is high risk for incurable relapse within two years.

2. Participants are germline HLA-A*02 heterozygous confirmed by HLA typing.

3. Primary tumor tissue showing LOH of HLA-A*02 by NGS testing.

4. Eastern Cooperative Oncology Group (ECOG) 0 or 1 performance status.

Part 2: Key Exclusion Criteria

1. History of any of other malignancy in the past 5 years other than non-melanoma skin
carcinoma, low grade localized prostate cancer, superficial bladder cancer, ductal
carcinoma in situ (CIS) of the breast, CIS of the Cervix, or Stage I uterine cancer.

2. Prior allogeneic stem cell transplant.

3. Prior solid organ transplant.

4. Participants who have received any cancer therapy on any investigational therapy for
any indication, including but not limited to chemotherapy, small molecules, monoclonal
antibodies, or radiotherapy (with bone marrow impact) within 2 weeks of planned
apheresis or 3 half-lives, whichever is shorter.

5. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
(excluding fungal infections of nail beds) at study enrollment necessitating specific
treatment, or any major episode of infection requiring treatment with Intravenous (IV)
antimicrobials (e.g., IV antibiotics) or hospitalization (relating to completion of
antibiotic course).

6. Has known active central nervous system metastases. Subjects with previously treated
brain metastases may participate upon medical monitor agreement.

7. In the Investigator's judgement, any other condition or reason the subject would not
complete the required study visits and procedures, and follow up visits, or comply
with the study requirements for participation.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 3/10/23. Questions regarding updates should be directed to the study team contact.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location	Status	Contact
Rochester, Minn. Mayo Clinic principal investigator Julian Molina, M.D., Ph.D.	Open for enrollment	Contact information: Cancer Center Clinical Trials Referral Office 855-776-0015
Jacksonville, Fla. Mayo Clinic principal investigator Hemant Murthy, M.D.	Open for enrollment	Contact information: Cancer Center Clinical Trials Referral Office (855) 776-0015

Mayo Clinic Location

Status

Contact

Rochester, Minn.

Mayo Clinic principal investigator

Julian Molina, M.D., Ph.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

855-776-0015

Jacksonville, Fla.

Mayo Clinic principal investigator

Hemant Murthy, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

We describe an approach to cancer therapy based on exploitation of common losses of genetic material in tumor cells (loss of heterozygosity) (Basilion et al., 1999; Beroukhim et al., 2010). This therapeutic concept addresses the fundamental problem of discrimination between tumor and normal cells and can be applied in principle to the large majority of tumors. It utilizes modular activator/blocker elements that integrate signals related to the presence and absence of ligands displayed on the cell surface (Fedorov et al., 2013). We show that the targeting system works robustly in vitro and in a mouse cancer model where absence of the HLA-A*02 allele releases a brake on engineered T cells activated by the CD19 surface antigen. This therapeutic approach potentially opens a route toward a large, new source of cancer targets. Read More on PubMed
Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer. Read More on PubMed
Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT. Read More on PubMed
A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types. Read More on PubMed

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