p95HER2–T cell bispecific antibody for breast cancer treatment

Ruiz, Irene Rius; Vicario, Rocío; Morancho, Beatriz; Bernadó-Morales, Cristina; Arenas, Enrique J.; Herter, Sylvia; Freimoser–Grundschober, Anne; Somandin, Jitka; Sam, Johannes; Ast, Oliver; Martínez-Barriocanal, Águeda; Luque, Antonio; Escorihuela, Marta; Varela, Ismael; Cuartas, Isabel; Nuciforo, Paolo; Fasani, Roberta; Peg, Vicente; Rubio, Isabel T.; Cortés, Javier; Serra, Violeta; Escrivá-de-Romaní, Santiago; Sperinde, Jeff; Chenna, Ahmed; Huang, Weidong; Winslow, John; Albanell, Joan; Seoane, Joan; Scaltriti, Maurizio; Baselga, José; Tabernero, Josep; Umaña, Pablo; Bacac, Marina; Saura, Cristina; Klein, Christian; Arribas, Joaquı́n

doi:10.1126/scitranslmed.aat1445

Cited by 71 publications

(37 citation statements)

References 38 publications

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“…We have previously described the so-called 2:1 TCBs that carry two tumor antigen binding moieties and a single CD3 binding moiety in an IgG-based format (33,34). This 2:1 format shows advantageous properties over classical 1:1 TCBs (9).…”

Section: Introductionmentioning

confidence: 99%

Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity

et al. 2020

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T-cell Bispeciﬁc Antibodies (TCBs) elicit anti-tumor responses by cross-linking T-cells to tumor cells and mediate polyclonal T-cell expansion that is independent of T-cell receptor specificity. TCBs thus offer great promise for patients who lack antigen-speciﬁc T-cells or have non-inflamed tumors, which are parameters known to limit the response of checkpoint inhibitors. The current study deepens the understanding of TCB mode of action and elaborates on one of the adaptive resistance mechanisms following its treatment in vivo in humanized mice and syngeneic pre-clinical tumor models. Single-agent TCB treatment reduced tumor growth compared with controls and led to a 2–10-fold increase in tumor-infiltrating T-cells, regardless of the baseline tumor immune cell infiltration. TCB treatment strongly induced the secretion of CXCL10 and increased the frequency of intra-tumor CXCR3+ T-cells pointing to the potential role of the CXCL10-CXCR3 pathway as one of the mechanisms for T-cell recruitment to tumors upon TCB treatment. Tumor-infiltrating T-cells displayed a highly activated and proliferating phenotype, resulting in the generation of a highly inflamed tumor microenvironment. A molecular signature of TCB treatment was determined (CD8, PD-1, MIP-a, CXCL10, CXCL13) to identify parameters that most robustly characterize TCB activity. Parallel to T-cell activation, TCB treatment also led to a clear upregulation of PD-1 on T-cells and PD-L1 on tumor cells and T-cells. Combining TCB treatment with anti-PD-L1 blocking antibody improved anti-tumor efficacy compared to either agent given as monotherapy, increasing the frequency of intra-tumoral T-cells. Together, the data of the current study expand our knowledge of the molecular and cellular features associated with TCB activity and provide evidence that the PD-1/PD-L1 axis is one of the adaptive resistance mechanisms associated with TCB activity. This mechanism can be managed by the combination of TCB with anti-PD-L1 blocking antibody translating into more efficacious anti-tumor activity and prolonged control of the tumor outgrowth. The elucidation of additional resistance mechanisms beyond the PD-1/PD-L1 axis will constitute an important milestone for our understanding of factors determining tumor escape and deepening of TCB anti-tumor responses in both solid tumors and hematological disorders.

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Section: Introductionmentioning

confidence: 99%

Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity

et al. 2020

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“…These 2:1 (target cell antigen:CD3ε) TRBAs have been dubbed by Roche as “TCBs,” for “T-cell Bispecifics.” There are currently two clinical stage TCBs that incorporate the Fab as an extra appendage, including cibisatamab (aka RG7802, RO6958688, CEA TCB) [159,204], which has two binding arms for CEA and a single binding arm for CD3ε and RG6026 (aka RO7082859) [205], which has two binding arms for CD20 and one for CD3ε [160]. Two additional TCBs, one targeting BCMA [206] and another targeting a carboxyl-terminal fragment of HER2 expressed in about half of HER2-positive tumors [207], have been reported but are not yet in clinical trials.…”

Section: T-cell Redirecting Bispecific Antibodies (Trbas)mentioning

confidence: 99%

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

2019

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The concepts for T-cell redirecting bispecific antibodies (TRBAs) and chimeric antigen receptor (CAR)-T cells are both at least 30 years old but both platforms are just now coming into age. Two TRBAs and two CAR-T cell products have been approved by major regulatory agencies within the last ten years for the treatment of hematological cancers and an additional 53 TRBAs and 246 CAR cell constructs are in clinical trials today. Two major groups of TRBAs include small, short-half-life bispecific antibodies that include bispecific T-cell engagers (BiTE®s) which require continuous dosing and larger, mostly IgG-like bispecific antibodies with extended pharmacokinetics that can be dosed infrequently. Most CAR-T cells today are autologous, although significant strides are being made to develop off-the-shelf, allogeneic CAR-based products. CAR-Ts form a cytolytic synapse with target cells that is very different from the classical immune synapse both physically and mechanistically, whereas the TRBA-induced synapse is similar to the classic immune synapse. Both TRBAs and CAR-T cells are highly efficacious in clinical trials but both also present safety concerns, particularly with cytokine release syndrome and neurotoxicity. New formats and dosing paradigms for TRBAs and CAR-T cells are being developed in efforts to maximize efficacy and minimize toxicity, as well as to optimize use with both solid and hematologic tumors, both of which present significant challenges such as target heterogeneity and the immunosuppressive tumor microenvironment.

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“…Rius Ruiz and colleagues have developed a TCB against p95HER2 (p95HER2-TCB) that has a potent anti-tumor effect on breast tumors expressing p95HER2, both in vitro and in vivo . 54 In contrast with HER2, p95HER2 is not expressed in normal tissues, therefore, it has no effect on nontumor cells that do not overexpress HER2. Those findings support further investigation with this compound.…”

Section: Novel Strategies To Overcome Resistance To Her2-targeted Thementioning

confidence: 99%

HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance

2019

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The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody–drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.

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p95HER2–T cell bispecific antibody for breast cancer treatment

Cited by 71 publications

References 38 publications

Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity

Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance

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