Development of Cell and Gene Therapies for Clinical Use in the US and EU: Summary of Regulatory Guidelines.

Recent decades have seen advancements in the management and treatment of difficult-- to-treat diseases such as cancer. A special class of therapeutics called cell and gene therapy has been introduced in the past 10 years. Cell and gene therapy products have strengthened the treatment options for life-threatening diseases with unmet clinical needs and also provided the possibility of a potential cure for the disease in some of the patients. Cell and gene therapy products are gaining recognition, and the interest in clinical development of cell and gene therapy products is increasing. Moreover, as the class of cell and gene therapy products is relatively new, there is a limited regulatory experience in the development, and the developers of the cell and gene therapy products can often be puzzled with an array of questions on regulations. The current review intends to provide a basic understanding of regulatory guidelines from the FDA and EMA that are applicable to cell and gene therapy products. Essentials such as which office is responsible for the evaluation of applications, which regulatory class/pathway is appropriate for development, and what are the quality, nonclinical and clinical studies that are needed to support the application are discussed in the article. In addition, a summary of regulatory designations and the post-approval requirements, such as Risk Evaluation and Mitigation Strategies (REMS) and long-term follow- up, is included in the article. Developers (referred to as 'sponsors' in this article) of cell and gene therapies can use the respective guidance documents and other specific review articles cited in this review for detailed information on the topics.

Optimizing outcomes and managing adverse events in locally advanced or metastatic urothelial cancer: a clinical pharmacology perspective.

INTRODUCTION: Bladder cancer (BC) is the sixth most common type of cancer with epithelial/urothelial and non-urothelial origins. Urothelial carcinoma (UC) involves neoplastic cells of epithelial origin and accounts for 90% of all BC cases. Current review aims to discuss the latest advances and challenges in the treatment of UC with an emphasis on clinical pharmacology considerations. AREAS COVERED: Data including clinical efficacy and safety outcomes as well as precautions reported in published clinical studies obtained from PubMed and package inserts were collected and summarized in the review. Recent decade saw the approval of multiple drugs for the treatment of BC in both adjuvant/neoadjuvant setting as well as for unresectable tumors. Checkpoint blockers (pembrolizumab, nivolumab, atezolizumab, and avelumab), antibody drug conjugates (enfortumab vedotin and sacituzumab govitecan) and targeted therapies (erdafitinib) are now available in first-line (cisplatin-ineligible), second-line and third-line settings along with conventional platinum-based chemotherapy. While the survival outcomes have improved especially in refractory and unresponsive patients, the response rates are relatively low and patient safety needs further optimization. EXPERT OPINION: Additional studies on combination therapies, dose adjustments in special populations and impact of anti-drug antibodies on drug exposure are needed to further improve clinical outcomes.

Dose fractionation of CAR-T cells. A systematic review of clinical outcomes.

CAR-T cells are widely recognized for their potential to successfully treat hematologic cancers and provide durable response. However, severe adverse events such as cytokine release syndrome (CRS) and neurotoxicity are concerning. Our goal is to assess CAR-T cell clinical trial publications to address the question of whether administration of CAR-T cells as dose fractions reduces toxicity without adversely affecting efficacy. Systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematologic cancers. Studies published in English were considered. Studies in children (age < 18), solid tumors, bispecific CAR-T cells, and CAR-T cell cocktails were excluded. Data was extracted from the studies that met inclusion and exclusion criteria. Review identified a total of 18 studies that used dose fractionation. Six studies used 2-day dosing schemes and 12 studies used 3-day schemes to administer CAR-T cells. Three studies had both single dose and fractionated dose cohorts. Lower incidence of Grade ≥ 3 CRS and neurotoxicity was seen in fractionated dose cohorts in 2 studies, whereas 1 study reported no difference between single and fractionated dose cohorts. Dose fractionation was mainly recommended for high tumor burden patients. Efficacy of CAR-T cells in fractionated dose was comparable to single dose regimen within the same or historical trial of the same agent in all the studies. The findings suggest that administering dose fractions of CAR-T cells over 2-3 days instead of single dose infusion may mitigate the toxicity of CAR-T cell therapy including CRS and neurotoxicity, especially in patients with high tumor burden. However, controlled studies are likely needed to confirm the benefits of dose fractionation.

Dose-response correlation for CAR-T cells: a systematic review of clinical studies.

The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently under clinical development, with most in early stage, during which dose selection is a key goal. The objective of this review is to address the question of dose-dependent effects on response and/or toxicity from available CAR-T cell clinical trial data. For that purpose, systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematological cancers. Studies published in English were considered. Studies in children (age <18 years), solid tumors, bispecific CAR-T cells and CAR-T cell cocktails were excluded. As a result, a total of 74 studies met the inclusion criteria. Thirty-nine studies tested multiple dose levels of CAR-T cells with at least >1 patient at each dose level. Thirteen studies observed dose-related increase in disease response and 23 studies observed dose-related increase in toxicity across a median of three dose levels. Optimal clinical efficacy was seen at doses 50-100 million cells for anti-CD19 CAR-T cells and >100 million cells for anti-BCMA CAR-T cells in majority of studies. The findings suggest, for a given construct, there exists a dose at which a threshold of optimal efficacy occurs. Dose escalation may reveal increasing objective response rates (ORRs) until that threshold is reached. However, when ORR starts to plateau despite increasing dose, further dose escalation is unlikely to result in improved ORR but is likely to result in higher incidence and/or severity of mechanistically related adverse events.

Concept of the Number Needed to Treat for the Analysis of Pain Relief Outcomes in Patients Treated with Spinal Cord Stimulation.

In the rapidly evolving field of spinal cord stimulation (SCS), measures of treatment effects are needed to help understand the benefits of new therapies. The present article elaborates the number needed to treat (NNT) concept and applies it to the SCS field. We reviewed the basic theory of the NNT, its calculation method, and its application to historical controlled trials of SCS. We searched the literature for controlled studies with ≥20 implanted SCS patients with chronic axial back and/or leg pain followed for ≥3 months and a reported responder rate defined as ≥50% pain relief. Relevant data necessary to estimate the NNT were extracted from the included articles. In total, 12 of 1616 records were eligible for inclusion. The records reported 10 clinical studies, including 7 randomized controlled trials, 2 randomized crossover trials, and 1 controlled cohort study. The studies investigated traditional SCS and more recently developed SCS modalities, including 10 kHz SCS. In conclusion, the NNT estimate may help SCS stakeholders better understand the effect size difference between compared treatments; however, interpretation of any NNT should take into account its full context. In addition, comparisons across trials of different therapies should be avoided since they are prone to interpretation biases.

Safety and Efficacy of 10 kHz Spinal Cord Stimulation for the Treatment of Refractory Chronic Migraine: A Prospective Long-Term Open-Label Study.

BACKGROUND: Refractory chronic migraine (rCM) is a highly disabling condition for which novel safe and effective treatments are needed. Safety and long-term efficacy of paresthesia-free high cervical 10 kHz spinal cord stimulation (SCS) were here prospectively evaluated for the treatment of rCM. MATERIALS AND METHODS: Twenty adults with rCM (mean numbers of preventive treatments failed: 12.2 ± 3.1) were enrolled in this single-center, open-label, prospective study and implanted with a 10 kHz SCS system (Senza™ system, Nevro Corp), with the distal tip of the lead(s) positioned epidurally at the C2 vertebral level. Safety and effectiveness outcomes, such as adverse events, headache and migraine reductions, responder rates, Migraine Disability Assessment (MIDAS), Headache Impact Test-6 (HIT-6), and Migraine-Specific Quality-of-Life (MSQ), were captured up to 52 weeks after implantation. RESULTS: Compared to baseline, at 52 weeks postimplantation, there was a significant reduction of mean monthly migraine days (MMD) by 9.3 days (p < 0.001). Sixty percent and 50% of patients obtained respectively at least 30% and at least 50% reduction in mean MMD. By week 52, 50% of patients' chronic pattern converted to an episodic pattern. The proportion of subjects classified with severe headache-related disability on the HIT-6, decreased from 100% to 60% at week 52. Meaningful improvements of headache-related quality of life measured by the MSQ scale were observed with mean gain of 24.9 ± 23.1 (p < 0.001) points at 52 weeks. No unanticipated adverse device effects occurred. No patients required any additional device surgical revision. CONCLUSION: 10 kHz SCS may a be safe and effective neurostimulation option for rCM patients. The paresthesia-free waveform constitutes an unprecedented advantage for future methodologically sound sham-controlled studies in headache neuromodulation.

High-frequency (10 kHz) spinal cord stimulation for the treatment of focal, chronic postsurgical neuropathic pain: results from a prospective study in Belgium.

Aim: Chronic postsurgical pain (CPSP) is a common complication of surgery. This study was conducted to evaluate the efficacy and safety of paresthesia-free, 10-kHz spinal cord stimulation (SCS) as a treatment for CPSP. Patients & methods: Subjects in this prospective, single-arm study had an average pain intensity of ≥5 cm on a 10-cm visual analog scale. The subjects who had pain relief of ≥50% (response) with temporary trial stimulation were permanently implanted with 10-kHz SCS and assessed for 1 year. Results: At 12 months, 94% of subjects were responders to 10-kHz SCS, and 88% had pain remission (visual analog scale ≤2.5 cm). Conclusion: The pain relief was durable in CPSP subjects and the safety profile of 10-kHz SCS was as expected. Clinical Trial registration number: VT005076953 (Privacy Commission of Belgium).

Pharmacology-based ranking of anti-cancer drugs to guide clinical development of cancer immunotherapy combinations.

The success of antibodies targeting Programmed cell death protein 1 (PD-1) and its ligand L1 (PD-L1) in cancer treatment and the need for improving response rates has led to an increased demand for the development of combination therapies with anti-PD-1/PD-L1 blockers as a backbone. As more and more drugs with translational potential are identified, the number of clinical trials evaluating combinations has increased considerably and the demand to prioritize combinations having potential for success over the ones that are unlikely to be successful is rising. This review aims to address the unmet need to prioritize cancer immunotherapy combinations through comprehensive search of potential drugs and ranking them based on their mechanism of action, clinical efficacy and safety. As lung cancer is one of the most frequently studied cancer types, combinations that showed potential for the treatment of lung cancer were prioritized. A literature search was performed to identify drugs with potential in combination with PD-1/PD-L1 blockers and the drugs were ranked based on their mechanism of action and known clinical efficacy. Nineteen drugs or drug classes were identified from an internal list of lead molecules and were scored for their clinical potential. Efficacy and safety data from pivotal studies was summarized for the selected drugs. Further, overlap of mechanisms of action and adverse events was visualized using a heat map illustration to help screen drugs for combinations. The quantitative scoring methodology provided in this review could serve as a template for preliminary ranking of novel combinations.

Targeting TIGIT for Immunotherapy of Cancer: Update on Clinical Development.

Immune checkpoint blockers have dramatically improved the chances of survival in patients with metastatic cancer, but only a subset of the patients respond to treatment. Search for novel targets that can improve the responder rates and overcome the limitations of adverse events commonly seen with combination therapies, like PD-1 plus CTLA-4 blockade and PD-1/PD-L1 plus chemotherapy, led to the development of monoclonal antibodies blocking T-cell immunoglobulin and ITIM domain (TIGIT), a inhibitory checkpoint receptor expressed on activated T cells and NK cells. The strategy showed potential in pre-clinical and early clinical studies, and 5 molecules are now in advanced stages of evaluation (phase II and above). This review aims to provide an overview of clinical development of anti-TIGIT antibodies and describes the factors considered and thought process during early clinical development. Critical aspects that can decide the fate of clinical programs, such as origin of the antibody, Ig isotype, FCγR binding, and the dose as well as dosing schedule, are discussed along with the summary of available efficacy and safety data from clinical studies and the challenges in the development of anti-TIGIT antibodies, such as identifying patients who can benefit from therapy and getting payer coverage.

Decreased Opioid Consumption and Durable Pain Relief in Patients Treated with 10 kHz SCS: A Retrospective Analysis of Outcomes from Single-Center.

BACKGROUND: Chronic pain is frequently treated with opioid analgesics, but there is limited evidence for efficacy for chronic use of opioids and the drugs pose significant risks to patients' physical and mental health. Spinal cord stimulation delivered at a frequency of 10,000 Hertz (10 kHz SCS) is a minimally invasive therapy with demonstrated efficacy and safety in treating chronic pain that has also been associated with decreased opioid use. OBJECTIVE: To evaluate opioid reduction and pain relief in real-world cohort. STUDY DESIGN: Retrospective review. SETTING: Single center. PATIENTS AND METHODS: Consecutive patients who were implanted with 10 kHz SCS devices from December 1, 2015, to June 30, 2020 for the treatment of chronic pain in the trunk or lower limbs were included. Changes in opioid use following 10 kHz SCS treatment were extracted from electronic medical records, and patient-reported pain relief, improvement in function and sleep were extracted from manufacturer's database. Responder rate was defined as the proportion of patients with at least 50% pain relief. Anonymised results from descriptive analysis of the data are reported. RESULTS: At last follow-up (median 21.4 months), mean daily opioid dose fell by 48.4 morphine milligram equivalents (MME), and fewer patients used opioids. Mean pain relief in these patients was 57% ± 4%, and responder rate was 68% at last recorded follow-up. Interestingly, pain relief (66%) and responder rate (86%) were higher in patients with 1 year or more. Finally, 50% of patients reported improved sleep, and 73% reported improvement in function at last recorded follow-up after treatment with 10 kHz SCS. CONCLUSION: These results support 10 kHz SCS as a safe and effective treatment of chronic pain in real-world patients with secondary benefits to opioid consumption and measures of patients' quality of life.

Efficacy and Safety of 10 kHz Spinal Cord Stimulation Using Cervical and Thoracic Leads: A Single-Center Retrospective Experience.

INTRODUCTION: Spinal cord stimulation (SCS) with lower thoracic leads has been studied extensively. However, the evidence base for cervical SCS is less well developed, and reports of multiarea SCS lead placement are uncommon. Therefore, this single-center retrospective study evaluated outcomes from 10-kHz SCS with cervical or combined cervical and thoracic lead placement. METHOD: All patients that underwent a 10-kHz SCS trial with either cervical or combined cervical and thoracic lead placement between 2015 and 2020 were included in our study. We reviewed patient's charts for demographic information, lead placement, and pain scores up to 48 months after implantation. RESULTS: Of the 105 patients that underwent a 10-kHz SCS trial during the review period, 92 (88%) had back/neck or extremity pain that responded to therapy (≥ 50% pain relief from baseline) and received a permanent system. Sixty-two of these patients (67%) were implanted with combined cervical and thoracic leads, while 30 (33%) received cervical-only leads. Pain relief in both regions exceeded 60% at most visits throughout the 48-month study period. Throughout follow-up, the responder rate in both pain areas was consistently ≥ 70%. No unexpected adverse events occurred. CONCLUSION: The 10-kHz SCS provided effective and durable pain relief with either cervical or combined cervical and thoracic leads. The efficacy and safety profile of both applications appears to be comparable to lower thoracic SCS. Our results suggest that 10-kHz SCS is a useful paresthesia-free therapeutic option for chronic neuropathic pain originating in the cervical area, as well as more complex multiarea pain presentations.

Amelioration of lower limb pain and foot drop with 10 kHz spinal cord stimulation: A case series.

There are limited treatment options for patients with foot drop and associated lower back and/or leg pain. We present a case series of three patients who received permanent implantation of 10 kHz spinal cord stimulation (10 kHz SCS) devices. Following treatment, all patients reported sustained improvements in lower back and leg pain, foot mechanics and function which resulted in increased mobility and cessation of opioid use for pain management. Patients were followed up for approximately four years. Treatment with 10 kHz SCS may be a promising alternative to other interventional procedures commonly used for these patients.

Pain Relief and Safety Outcomes with Cervical 10 kHz Spinal Cord Stimulation: Systematic Literature Review and Meta-analysis.

BACKGROUND: Chronic pain in head, neck, shoulders and upper limbs is debilitating, and patients usually rely on pain medications or surgery to manage their symptoms. However, given the current opioid epidemic, non-pharmacological interventions that reduce pain, such as spinal cord stimulation (SCS), are needed. The purpose of this study was to review the evidence on paresthesia-free 10 kHz SCS therapy for neck and upper extremity pain. METHODS: Systematic literature search was performed for studies reporting outcomes for cervical 10 kHz SCS using date limits from May 2008 to November 2020. The study results were analyzed and described qualitatively. Additionally, when feasible, meta-analyses of the outcome data, with 95% confidence intervals (CIs), were conducted using both the fixed-effects (FE) and random-effects (RE) models. RESULTS: A total of 15 studies were eligible for inclusion. The proportion of patients who achieved ≥ 50% pain reduction was 83% (95% CI 77-89%) in both the FE and RE models. The proportion of patients who reduced/eliminated their opioid consumption was 39% (95% CI 31-46%) in the FE model and 39% (95% CI 31-48%) in the RE model. Pain or discomfort with the implant, lead migration, and infections were potential risks following cervical SCS. Explant rate was 0.1 (95% CI 0.0-0.2) events per 100 person-months, and no patients in the included studies experienced a neurological complication or paresthesia. CONCLUSION: Findings suggest 10 kHz SCS is a promising, safe, minimally invasive alternative for managing chronic upper limb and neck pain.

A Retrospective Review of Lead Migration Rate in Patients Permanently Implanted with Percutaneous Leads and a 10 kHz SCS Device.

Background: Spinal cord stimulation (SCS) has been used over decades for pain management, but migration of percutaneous leads has been the most common complication. Better surgical techniques and newer SCS technologies likely reduced the incidence of lead migration requiring surgical revision, although data are sparse. This study aimed to retrospectively evaluate the incidence of clinically significant percutaneous lead migration in patients permanently implanted with a 10 kHz SCS system. Methods: Consecutive patients with chronic trunk and/or limb pain, permanently implanted between January 2016 and June 2019, were included in the analysis. Data were collected from the hospital's electronic medical records and the manufacturer's database. Clinically significant lead migration, defined as diminished pain relief followed by surgery to correct lead location, was assessed at the 6-month follow-up. Results: At the 6-month follow-up, there were no cases of clinically significant lead migration, average pain relief was 65.2%, 82% of patients had response (≥50% pain relief), improvement of function was noted in 72% of patients, and decrease of medication was observed in 42% of patients. Therapy efficacy was sustained in patients with >12 months follow-up; the average pain relief was 58.5%, and the response rate was 82%. Conclusions: The surgical techniques in use today are designed to minimise the risk of percutaneous lead migration and may have reduced its incidence. In addition, new SCS systems may give greater opportunity to mitigate cases of minor lead movement using alternative stimulation programs.

10 kHz Spinal Cord Stimulation for the Treatment of Failed Back Surgery Syndrome with Predominant Leg Pain: Results from a Prospective Study in Patients from the Dutch Healthcare System.

INTRODUCTION: Persistent back/and or leg pain is a common outcome after spinal surgery (otherwise known as failed back surgery syndrome [FBSS]). Studies have shown that spinal cord stimulation (SCS) at 10 kHz provides effective analgesia in FBSS patients with both back and leg pain symptoms and in those with predominant back pain. This study is the first to evaluate the therapy in FBSS patients with predominant leg pain. METHODS: The safety and efficacy of 10 kHz SCS was evaluated in an uncontrolled, open-label, prospective study of FBSS patients with predominant leg pain in the Netherlands. Follow-ups were performed at 1, 3, 6, and 12 months post implantation. RESULTS: Sixty out of 68 patients (88%) experienced sufficient pain relief during a stimulation trial. Of these, 58 proceeded to permanent implantation of a 10 kHz SCS system. After 12 months of treatment, 80% of patients experienced ≥ 50% reduction in baseline leg pain, and a similar proportion (76%) experienced ≥ 50% reduction in baseline back pain. At least two-thirds of patients were also leg pain and back pain remitters (visual analog scale [VAS] ≤ 2.5 cm). The therapy was also associated with a general improvement in patients' quality of life, as measured by secondary outcomes including disability, perception of health improvement, mental well-being, and satisfaction. A positive impact on opioid consumption was also observed. CONCLUSIONS: Consistent with previous findings, 10 kHz SCS for the treatment of FBSS patients with predominant radicular symptoms is safe and effective and is associated with improved quality of life.

A Prospective, Multi-Center, Clinical Trial of a 10-kHz Spinal Cord Stimulation System in the Treatment of Chronic Pelvic Pain.

BACKGROUND: Chronic pelvic pain (CPP) is a debilitating condition that often leads to disability and does not respond to conventional treatments. This study was conducted to evaluate the effects of paresthesia-independent 10-kHz spinal cord stimulation (SCS) in subjects with CPP. METHODS: This prospective, single-arm pilot study enrolled subjects with clinical diagnoses of CPP and mean pain scores of ≥ 5.0 cm on a 10-cm VAS. Subjects underwent trial stimulations with 10-kHz SCS, and those who had successful trial stimulations (≥40% pain relief) received permanently implanted devices and were followed for 12 months. RESULTS: Of the 21 subjects who underwent the 10-kHz SCS trial, 17 were successful and 14 subjects received permanent implants. No neurological deficits were observed in any subjects and all adverse events (AEs) were resolved without sequelae during the study period. Over 12 months, mean VAS scores decreased by 72% from baseline, and 10 of 13 subjects (77%) were responders (≥50% pain relief). Pain remission (VAS score ≤ 3.0 cm) was reported by 8 of 13 subjects (62%), and mean pain scores on the short-form McGill Pain Questionnaire 2 decreased as well. Pain Disability Index scores declined by 29 points, and 85% of the subjects reported satisfaction. CONCLUSIONS: Paresthesia-independent stimulation with 10-kHz SCS reduced pelvic pain in subjects with CPP and was not associated with any unexpected AEs. While larger, controlled studies are needed, results of this study suggest that this therapeutic modality could potentially treat patients with CPP while improving their quality of life.

Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities.

Tremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies that activate and expand antigen-specific CD8+ and CD4+ T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clinical practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. Intravenous or intramuscular administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quantitative methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome.

Pain relief and opioid usage in upper limb and neck pain patients after 10-kHz spinal cord stimulation treatment: subanalysis of USA studies.

Aim: It is argued that chronic pain patients who reduce/eliminate their opioids may have compromised pain relief. This study therefore aimed to analyze if reduced opioid consumption associated with 10-kHz spinal cord stimulation adversely affected pain relief. Methods: Post hoc analysis was performed on data from two prospective studies in subjects with upper limbs and neck pain conducted in USA. Results & conclusion: A 10-kHz spinal cord stimulation treatment was associated with reduction in mean visual analog scale scores for upper limbs and neck pain and mean daily opioid consumption. Pain scores decreased in subjects who decreased opioid use and in those who maintained/increased use. Opioid reduction and pain relief was also achieved in subjects taking >90 mg morphine equivalents of opioids at baseline.