Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy

Caswell-Jin, Jennifer L.; McNamara, Katherine; Reiter, Johannes G.; Sun, Ruping; Hu, Zheng; Ma, Zhicheng; Ding, Jie; Suarez, Carlos J.; Tilk, Susanne; Raghavendra, Akshara Singareeka; Forte, Victoria; Chin, Suet Feung; Bardwell, Helen; Provenzano, Elena; Caldas, Carlos; Lang, Julie E.; West, Robert B.; Tripathy, Debasish; Press, Michael F.; Curtis, Christina

doi:10.1038/s41467-019-08593-4

Cited by 48 publications

(53 citation statements)

References 67 publications

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“…Alternatively, COBRAs that target two different tumor antigens could address the problem of acquired resistance due to the heterogeneous nature of protein expression within human tumors. [48][49][50][51][52][53] To address this problem, COBRAs would contain two tumor-targeting sdAbs, each of which is able to induce potent T cell engagement alone. Such molecules would exert anti-tumor activity on tumor cells that express either antigen, and, as a result, would be expected to have activity on a broader range of tumors cells than COBRAs that target a single antigen.…”

Section: Discussionmentioning

confidence: 99%

COBRA™: a highly potent conditionally active T cell engager engineered for the treatment of solid tumors

Panchal¹,

Seto²,

Wall³

et al. 2020

mAbs

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Conditionally active COBRA™ (COnditional Bispecific Redirected Activation) T cell engagers are engineered to overcome the limitations of inherently active first-generation T cell engagers, which are unable to discern between tumor and healthy tissues. Designed to be administered as prodrugs, COBRAs target cell surface antigens upon administration, but engage T cells only after they are activated within the tumor microenvironment (TME). This allows COBRAs to be preferentially turned on in tumors while safely remaining inactive in healthy tissue. Here, we describe the development of the COBRA design and the characterization of these conditionally active T cell engagers. Upon administration COBRAs are engineered to bind to tumor-associated antigens (TAAs) and serum albumin (to extend their half-life in circulation), but are inhibited from interacting with the T cell receptor complex signaling molecule CD3. In the TME, a matrix metalloproteinase (MMP)-mediated linker cleavage event occurs within the COBRA construct, which rearranges the molecule, allowing it to co-engage TAAs and CD3, thereby activating T cells against the tumor. COBRAs are conditionally activated through cleavage with MMP9, and once active are highly potent, displaying sub-pM EC 50 s in T cell killing assays. Studies in tumor-bearing mice demonstrate COBRA administration completely regresses established solid tumor xenografts. These results strongly support the further characterization of the novel COBRA design in preclinical development studies.

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Section: Discussionmentioning

confidence: 99%

COBRA™: a highly potent conditionally active T cell engager engineered for the treatment of solid tumors

Panchal¹,

Seto²,

Wall³

et al. 2020

mAbs

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“…However, T-DM1 plus pertuzumab was found not to be superior to trastuzumab plus taxane (the standard of care at trial initiation). While HER2 heterogeneity may explain attenuated clinical response rates in at least some patients with HER2þ breast cancer treated with T-DM1 (31)(32)(33)(34)(35) another compelling rationale is that T-DM1 doses simply were not high enough to fully-enable trastuzumab functions that meaningfully contribute to disease control (9). Our data suggest that CAT-01-106, with its superior tolerability and stability, might provide a solution to this problem and thus potentially enable better treatment outcomes and improved quality of life for patients.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, randomized trials of T-DM1 in gastric cancer (GATSBY trial) also failed to demonstrate superior efficacy compared with a taxane among 415 patients with previously-treated HER2 þ locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma treated in the second-line (30). Emerging clinical data strongly suggests that one mode of failure for T-DM1 for a fraction of patients in these studies is intratumoral HER2 heterogeneity (31)(32)(33)(34)(35)(36). Nonetheless, these outcomes may also reflect the fact that T-DM1, while maintaining trastuzumab effector functions, may not adequately enable those functions in vivo due to toxicity-related dosing constraints (9).…”

Section: Introductionmentioning

confidence: 99%

A Novel HER2-targeted Antibody–drug Conjugate Offers the Possibility of Clinical Dosing at Trastuzumab-equivalent Exposure Levels

Barfield¹,

Kim²,

Chuprakov³

et al. 2020

Molecular Cancer Therapeutics

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Trastuzumab and the related ADC, ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2 þ breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload. Interestingly, in the clinic, T-DM1 cannot always replace the use of trastuzumab plus chemotherapy administered together as single agents. We hypothesize that this failure may be due, in part, to the limited systemic exposure achieved by T-DM1 relative to trastuzumab because of toxicity-related dosing constraints on the ADC. We have developed a trastuzumab-based ADC site specifically conjugated to maytansine through a noncleavable linker. This construct, termed CAT-01-106, has a drug-toantibody ratio (DAR) of 1.8, approximately half the average DAR of T-DM1, which comprises a mixture of antibodies variously conjugated with DARs ranging from 0 to 8. The high DAR species present in T-DM1 contribute to its toxicity and limit its clinical dose. CAT-01-106 showed superior in vivo efficacy compared with T-DM1 at equal payload dosing and was equally or better tolerated compared with T-DM1 at equal payload dosing up to 120 mg/kg in Sprague-Dawley rats and 60 mg/kg in cynomolgus monkeys. CAT-01-106 also showed improved pharmacokinetics in rats relative to T-DM1, with 40% higher ADC exposure levels. Together, the data suggest that CAT-01-106 may be sufficiently tolerable to enable clinical dosing at trastuzumab-equivalent exposure levels, combining the functions of both the antibody and the payload in one drug and potentially improving patient outcomes.

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“…The geographical expansion of mutant subclones was often confined to 1-3 adjacent regions, but interestingly in some cases, mutationally distinct subclones were found to be growing admixed with one another. Cases studied pre-and post-neoadjuvant chemotherapy or targeted therapy revealed evidence that treatment can dramatically alter the clonal make-up of a tumour [39,40].…”

Section: Subclonal Genomic Diversity In Primary Breast Cancermentioning

confidence: 99%

“…Pathologists already record the presence of mixed growth patterns or grades, or the diversity across a tumour for the expression of ER, PR, HER2. Comprehensive sequencing of the entire primary tumour to characterise the subclonal architecture of a mass is not feasible, but evidence suggests that sequencing of two different regions of the tumour provides meaningful information to record clonal heterogeneity and to identify targetable genomic alterations [40].…”

Section: Capturing Intra-tumour Heterogeneity In Tissue or Liquid Biopsymentioning

confidence: 99%

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

Kutasovic

Reed

Sokolova

et al. 2020

Cancers

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Breast cancer is a remarkably complex and diverse disease. Subtyping based on morphology, genomics, biomarkers and/or clinical parameters seeks to stratify optimal approaches for management, but it is clear that every breast cancer is fundamentally unique. Intra-tumour heterogeneity adds further complexity and impacts a patient’s response to neoadjuvant or adjuvant therapy. Here, we review some established and more recent evidence related to the complex nature of breast cancer evolution. We describe morphologic and genomic diversity as it arises spontaneously during the early stages of tumour evolution, and also in the context of treatment where the changing subclonal architecture of a tumour is driven by the inherent adaptability of tumour cells to evolve and resist the selective pressures of therapy.

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Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy

Cited by 48 publications

References 67 publications

COBRA™: a highly potent conditionally active T cell engager engineered for the treatment of solid tumors

COBRA™: a highly potent conditionally active T cell engager engineered for the treatment of solid tumors

A Novel HER2-targeted Antibody–drug Conjugate Offers the Possibility of Clinical Dosing at Trastuzumab-equivalent Exposure Levels

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

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