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NEWS AND PUBLICATIONS

The Hanahan and Weinberg “hallmarks of cancer” papers provide a useful structure for considering the various mechanisms driving cancer progression, and the same might be useful for wound healing. In this review, it is highlighted how tissue repair and cancer share cellular and molecular processes that are regulated in a wound but misregulated in cancer. From sustained proliferative signaling and the activation of invasion and angiogenesis to the promoting role of inflammation, there are many obvious parallels through which one process can inform the other. For some hallmarks, the parallels are more obscure. The authors propose some new prospective hallmarks that might apply to both cancer and wound healing and discuss how wounding, as in biopsy and surgery, might positively or negatively influence cancer in the clinic.

Fig. 2. How the hallmarks extrapolate to a healing wound. The contribution of the hallmarks and enabling characteristics to wound healing are mapped onto a schematic of a healing skin wound. Cell migration and proliferation drive re-epithelialization, which may also depend on altered cellular energetics. The wounded epithelium must also resist cell death and avoid damage inflicted by inflammatory cells that infiltrate the wound. Damage signals, the microbiome, and fat cells contribute to the inflammatory response, which, in turn, regulates both wound angiogenesis and matrix deposition.

While the effects of immune checkpoint blockade on the tumor microenvironment (TME) are widely investigated, the combined effect of chemotherapy and checkpoint blockade is less clear. Further, although the Impassion130 trial in advanced triple-negative breast cancer (TNBC) combining nab-paclitaxel with anti-PD-L1 therapy led to clear patient benefits and product approval, a similar trial (Impassion131) combining paclitaxel with anti-PD-L1 therapy did not, indicating that important distinctions still need to be understood. Therefore, Zhang, Chen, Mo, and Hu et al. comprehensively investigated the effects of paclitaxel and anti-PD-L1 on immune populations in the TME in TNBC. Their results were recently published in Cancer Cell. The researchers developed two indices, the predictive index (Pi), which measured the correlation between baseline cellular proportions with changes in tumor size, and the therapeutic index (Ti), which measured correlations between cellular proportion dynamics with tumor size changes. The Pi showed that B cells most accurately predicted favorable response to either treatment regimen, while the Ti showed that T cell changes correlated with therapy response to combination therapy.

(B) Immune features in responsive and nonresponsive tumors and their dynamics following different treatment regimens. TNBC tumors with substantial baseline CXCL13+ T cells, B cells, and proinflammatory macrophages would show sensitivity, in contrast to resistance of TNBC tumors with substantial immunosuppressive macrophages, to the combination therapy. Paclitaxel regimen decreased while atezolizumab increased key antitumor immune cells in responsive tumors (Zhang, Y et al. Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer, Cancer Cell, 2021, ISSN 1535-6108, https://doi.org/10.1016/j.ccell.2021.09.010).

(B) Immune features in responsive and nonresponsive tumors and their dynamics following different treatment regimens. TNBC tumors with substantial baseline CXCL13+ T cells, B cells, and proinflammatory macrophages would show sensitivity, in contrast to resistance of TNBC tumors with substantial immunosuppressive macrophages, to the combination therapy. Paclitaxel regimen decreased while atezolizumab increased key antitumor immune cells in responsive tumors (Zhang, Y et al. Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer, Cancer Cell, 2021, ISSN 1535-6108, https://doi.org/10.1016/j.ccell.2021.09.010).

INDUSTRY

Takeda to Acquire GammaDelta Therapeutics to Accelerate Development of Allogeneic γδT Cell Therapies Addressing Solid Tumors

Takeda Pharmaceutical Company Limited announced to acquire GammaDelta Therapeutics Limited, a company focused on exploiting the unique properties of gamma delta (γδ) T cells for immunotherapy. Through the acquisition, Takeda will obtain GammaDelta’s allogeneic variable delta 1 (Vδ1) gamma-delta (γδ) T cell therapy platforms, which includes both blood-derived and tissue-derived platforms, in addition to early-stage cell therapy programs. 

GammaDelta Therapeutics is a clinical stage biotechnology company pioneering the discovery and development of allogeneic γδT cell therapies for cancer. The company is developing an ‘off-the-shelf’ therapy based on one of the body’s own immune cells, a subtype of the γδ T-lymphocyte, known as the Vδ1+ T cell.

GammaDelta Therapeutics has developed a proprietary technologies to generate both blood-and tissue-derived allogeneic immunotherapies based on Vδ1 γδ T cells for the treatment of hematological malignancies and solid tumors.

Both platforms enabled the creation of non-engineered and genetically engineered allogeneic cell therapies, which demonstrate cellular activity and tumor cell killing capacity in pre-clinical models. GammaDelta is advancing its novel, γδ T cell platforms and product candidates under an ongoing collaboration with Takeda. GammaDelta’s technologies are based on pioneering world-class research conducted by Professor Adrian Hayday and Dr Oliver Nussbaumer, at King’s College London and the Francis Crick Institute, and Professor Bruno Silva-Santos at the University of Lisbon. Early-stage research was facilitated in part by the support and the infrastructure of the National Institute for Health Research Guy’s and St Thomas’ Biomedical Research Centre. The formation of GammaDelta as a company was supported by Cancer Research UK Commercial Partnerships.

https://gammadeltatx.com/the-science/

EMA

In October the CHMP made the following recommendatiosn on new medicines:

  • Conditional marketing authorisation for the medicinal product Rybrevant (Janssen-Cilag International N.V.) intended for the treatment of non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations. Rybrevant will be available as a 350 mg concentrate for solution for infusion. The active substance of Rybrevantis amivantamab, a fully human IgG1-based EGFR MET bispecific antibody that targets tumors with activating EGFR exon 20 insertion mutations. The benefits of Rybrevant are its objective response rate and response duration in NSCLC patients with EGFR exon 20 insertion mutations after failure of platinum-based therapy based on the CHRYSALIS-2 study.
  • Marketing authorization for the medicinal product Trodelvy (sacituzumab govitecan, Gilead Sciences Ireland UC) intended for the treatment of unresectable or metastatic triple-negative breast cancer (TNBC). Trodelvy was reviewed under EMA’s accelerated assessment program and is indicated for the treatment of adult patients with unresectable or metastatic TNBC who have received two or more prior systemic therapies, including at least one of them for advanced disease. The active substance of Trodelvy is sacituzumab govitecan, an antineoplastic agent. It combines a humanized monoclonal antibody, which binds to Trop‑2-expressing cancer cells, and a linked cytotoxic moiety SN-38 (govitecan), which inhibits topoisomerase I, preventing DNA repair and leading to apoptosis and cell death. The benefits of Trodelvy are its improved progression-free survival and overall survival in patients with unresectable locally advanced or metastatic TNBC which had relapsed after at least two prior chemotherapies, when compared with treatment of physician’s choice in the phase 3 ASCENT multicenter, open-label, randomized study.

Extension of indications for the following medicines:

  • Keytruda (pembrolizumab, Merck Sharp & Dohme B.V.) in combination with lenvatinib, is indicated for the first‑line treatment of advanced renal cell carcinoma in adults.
  • Keytruda (pembrolizumab, Merck Sharp & Dohme B.V.) with new indication approved in combination with lenvatinib, is indicated for the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum‑containing therapy in any setting and who are not candidates for curative surgery or radiation.
  • Kisplyx (lenvatinib; Eisai GmbH) is indicated for the treatment of adults with advanced renal cell carcinoma (RCC) in combination with pembrolizumab, as first-line treatment.
  • Lenvima (lenvatinib; Eisai GmbH) is indicated in combination with pembrolizumab is indicated for the treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery or radiation.

EMA updated guidance documents:

FDA

In October, the FDA granted approval for:

  • Tecartus (brexucabtagene autoleucel; Kite Pharma, Inc.) for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Efficacy was evaluated in ZUMA-3 (NCT02614066), a single-arm multicenter trial that evaluated brexucabtagene autoleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in adults with relapsed or refractory B-cell precursor ALL.  Patients received a single infusion of brexucabtagene autoleucel following completion of lymphodepleting chemotherapy. The efficacy outcome measures used to support approval were complete response (CR) achieved within 3 months from infusion and duration of CR. Of the 54 patients evaluable for efficacy, 28 (52%; 95% CI: 38, 66) achieved CR within 3 months. With a median follow-up for responders of 7.1 months, the median duration of CR was not reached; the duration of CR was estimated to exceed 12 months for more than half the patients.
  • Verzenio (abemaciclib; Eli Lilly and Company) with endocrine therapy (tamoxifen or an aromatase inhibitor) for adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score ≥20%, as determined by an FDA approved test. This is the first CDK 4/6 inhibitor approved for adjuvant treatment of breast cancer.

FDA also approved the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay, submitted by Agilent, Inc., as a companion diagnostic for selecting patients for this indication.

Efficacy was evaluated in monarchE (NCT03155997), a randomized (1:1), open-label, two-cohort multicenter trial that included adult women and men with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features consistent with a high risk of disease recurrence. Patients were randomized to receive either 2 years of abemaciclib plus their physician’s choice of standard endocrine therapy or standard endocrine therapy alone. The major efficacy outcome measure was invasive disease-free survival (IDFS). In patients with high risk of recurrence and Ki-67 Score ≥20% (N=2003), the trial demonstrated a statistically significant improvement in IDFS (HR 0.626; 95% CI: 0.488, 0.803; p=0.0042). IDFS at 36 months was 86.1% (95% CI: 82.8, 88.8) for patients receiving abemaciclib plus tamoxifen or an aromatase inhibitor and 79.0% (95% CI: 75.3, 82.3) for those receiving tamoxifen or an aromatase inhibitor. Overall survival data were not mature at the time of the IDFS analysis.

  • Keytruda (pembrolizumab; Merck) in combination with chemotherapy, with or without bevacizumab, for patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1), as determined by an FDA-approved test. FDA also granted regular approval to pembrolizumab as a single agent for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.  In June 2018, FDA had granted accelerated approval to this indication with the companion diagnostic, PD-L1 IHC 22C3 pharmDx (Dako North America Inc.). KEYNOTE-826 (NCT03635567), a multicenter, randomized, double-blind, placebo-controlled trial, examined pembrolizumab with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab. The trial enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy. Patients were enrolled irrespective of PD-L1 expression status. Patients were randomized (1:1) to one of two treatment groups: pembrolizumab 200 mg plus chemotherapy with or without bevacizumab or placebo plus chemotherapy with or without bevacizumab. Pembrolizumab was continued until disease progression, unacceptable toxicity, or 24 months of treatment. The main efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) assessed by the investigator using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional outcome measures were ORR and duration of response (DoR). For patients with tumors expressing PD-L1 (CPS ≥1, N=548), the median OS was not reached (95% CI: 19.8, NR) in the pembrolizumab arm and was 16.3 months (95% CI: 14.5, 19.4) in the placebo arm (HR 0.64; 95% CI: 0.50, 0.81; 1-sided p-value = 0.0001). Median PFS was 10.4 months (95% CI: 9.7, 12.3) in the pembrolizumab arm and 8.2 months (95% CI: 6.3, 8.5) in the placebo arm (HR 0.62; 95% CI: 0.50, 0.77; 1-sided p-value< 0.0001). The objective response rates were 68% (95% CI: 62, 74) and 50% (95% CI: 44, 56) with median DoR of 18.0 and 10.4 months in the pembrolizumab and placebo arms, respectively.
  • Tecentriq (atezolizumab; Genentech, Inc.) for adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II to IIIA non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA-approved test. The FDA also approved the VENTANA PD-L1 (SP263) Assay (Ventana Medical Systems, Inc.) as a companion diagnostic device to select patients with NSCLC for adjuvant treatment with Tecentriq. The major efficacy outcome measure was disease-free survival (DFS) as assessed by the investigator in the primary efficacy analysis population (n=476) of patients with stage II-IIIA NSCLC with PD-L1 expression on ≥1% of tumor cells (PD-L1 ≥1% TC). Median DFS was not reached (95% CI: 36.1, NE) in patients on the atezolizumab arm compared with 35.3 months (95% CI: 29.0, NE) on the BSC arm (HR 0.66; 95% CI: 0.50, 0.88; p=0.004).
  • Accelerated approval to Scemblix (asciminib; Novartis AG) for patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with two or more tyrosine kinase inhibitors (TKIs), and approved asciminib for adult patients with Ph+ CML in CP with the T315I mutation. ASCEMBL (NCT03106779), a multi-center, randomized, active-controlled, open-label clinical trial, is evaluating asciminib in patients with Ph+ CML in CP, previously treated with two or more TKIs. A total of 233 patients were randomized (2:1) and stratified according to major cytogenetic response (MCyR) status to receive either asciminib 40 mg twice daily or bosutinib 500 mg once daily. Patients continued treatment until unacceptable toxicity or treatment failure occurred. The main efficacy outcome measure was major molecular response (MMR) at 24 weeks. The MMR rate was 25% (95% CI: 19, 33) in patients treated with asciminib compared with 13% (95% CI: 6.5, 23; p=0.029) in those receiving bosutinib. With a median duration of follow-up of 20 months, the median duration of MMR has not yet been reached. CABL001X2101 (NCT02081378), a multi-center, open-label clinical trial, is evaluating asciminib in patients with Ph+ CML in CP with the T315I mutation. Efficacy was based on 45 patients with the T315I mutation who received asciminib 200 mg twice daily. Patients continued treatment until unacceptable toxicity or treatment failure occurred. The main efficacy outcome measure was MMR. MMR was achieved by 24 weeks in 42% (19/45, 95% CI: 28% to 58%) of the patients. MMR was achieved by 96 weeks in 49% (22/45, 95% CI: 34% to 64%) of the patients. The median duration of treatment was 108 weeks (range, 2 to 215 weeks).

FDA draft guidance documents of interest:

S1B(R1) Addendum to S1B Testing for Carcinogenicity of Pharmaceuticals

Addendum is to be used in close conjunction with ICH S1A Guideline on the Need for Carcinogenicity Studies for Pharmaceuticals, S1B Testing for Carcinogenicity of Pharmaceuticals, and S1C(R2) Dose Selection for Carcinogenicity Studies. The Addendum is complementary to the S1 Guidelines.

Data Standards for Drug and Biological Product Submissions Containing Real-World Data

The 21st Century Cures Act, signed into law on December 13, 2016, is intended to accelerate medical product development and bring innovations faster and more efficiently to the patients who need them. Among other provisions, the 21st Century Cures Act added section 505F to the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355g). Pursuant to this action, calling for FDA to issue guidance on the use of real-world evidence (RWE) in regulatory decision-making, FDA has created a framework for a program to evaluate the potential use of real-world data (RWD) to generate RWE to help support the approval of new indication(s) for drugs already approved under section 505(c) of the FD&C Act (21 U.S.C. 355(c)) or to help support or satisfy post-approval study requirements (RWE Program).

S12 Nonclinical Biodistribution Considerations for Gene Therapy Products

The objective of this guideline is to provide harmonized recommendations for the conduct of nonclinical biodistribution (BD) studies in the development of gene therapy (GT) products. This document provides recommendations for the overall design of nonclinical BD assessments. Considerations for interpretation and application of the BD data to support a nonclinical development program and the design of clinical trials are also provided. The recommendations in this guideline endeavor to facilitate the development of GT products while avoiding unnecessary use of animals, in accordance with the 3Rs (reduce/refine/replace) principles.

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