Enabling community‐based autologous adaptive immune cellular therapy manufactured at the point of care: A narrative review of global regulatory frameworks, affordability, and implementation strategy of a novel integrated facility and digital platform in the United States

Abbreviations

AABB

Association for the Advancement of Blood & Biotherapies

AAICT

autologous adaptive immune cellular therapy

AATB

American Association of Tissue Banks

ASTCT

American Society for Transplantation and Cellular Therapy

ATMP

advanced therapy medicinal product

BCPB

B‐cell plasmablasts

BCyIF

BioCytics immune fraction

BioDICE

BioCytics Digitally Integrated Clinical Enterprise

BLA

biologics license approval

CAR‐T

chimeric antigen receptor T cells

CBER

Center for Biologics Evaluation and Research

CBOI

Carolina BioOncology Institute, PLLC

CDER

Center for Drug Evaluation and Research

CDISC

Clinical Data Interchange Standards Consortium

CDMO

contract drug manufacturing organization

CFR

Code Federal Regulations

cGMP

current good manufacturing practice

C&GT

cell and gene therapies

CLIA

Clinical Laboratory Improvement Amendments of 1988

CMC

chemistry, manufacturing, and controls

CPF

cell processing facility

CRO

contract research organization

CTCs

circulating tumor cells

CTMS

clinical trial management system

CTRL

circulating tumor reactive lymphocytes

DM

distributed manufacturing

EBMT

European Bone Marrow Transplant Organization

EDC

electronic data capture system

EMA

European Medicines Agency

EMR

electronic medical record system

EMT

epithelial mesenchymal transition

Ex‐CLN

ex‐cellerator lymph node

FACT

Foundation of the Accreditation of Cellular Therapy

FDA

U.S. Food and Drug Administration

FHIR

Fast Healthcare Interoperability Resources

GCP

good clinical practice

GLP

good laboratory practice

HAL

human applications lab

HALIMS

human applications laboratory information management system

HCF

health care facility

HCT/Ps

human cells, tissues, or cellular or tissue‐based products

HE

Hospital Exemption

HIV

human immunodeficiency virus

HL7

health level seven

HLA

human leukocyte antigen

HPSCT

hematopoietic stem cell transplantation

HSPCs

hematopoietic stem and progenitor cells

ICB

Immune checkpoint blockade

ICH M11 CeSHarP

International Council of Harmonization, Multidisciplinary 11 Template, Clinical Electronic Structured Harmonized Protocol

ICT

immune cell therapy

IFNγ

interferon gamma

IND

investigational new drug

INTERACT

Initial Targeted Engagement for Regulatory Advice on CBER/CDER Products

IO

immuno‐oncology

iPSC

induced pluripotent stem cell

ISCT

International Society for Cell and Gene Therapy

JACIE

Joint Accreditation Committee ISCT‐Europe and EBMT

LKA

leukapheresis

LOINC

Logical Observation Identifier Names and Codes

MedDRA

Medical Dictionary of Regulatory Activities

MHRA

Medicines and Health Regulatory Agency (UK)

MM

modular manufacture

mNK

memory natural killer

MP

manufacturing platform

MRD

minimal residual disease

MU

manufacturing unit

non GM cells

nongenetically modified cells

OCN

oncology certified nurse

OHDSI

Observational Health Data Sciences and Informatics

openEHR

Open Electronic Health Records

PBMC

peripheral blood mononuclear cell

PDTO

patient‐derived tumor organoids

PoC

point‐of‐care

PPQ

process performance qualification

PQS

pharmaceutical quality system

QA

quality assurance

QC

quality control

QMS

quality management system

QU

quality unit

RMTM

rapid microbial testing methods

SNOMED

Systematized Nomenclature of Medicine

SOP

standard operating procedure

TAAs

tumor‐associated antigens

TCR

T‐cell receptor

TILs

tumor infiltrating lymphocytes

TMB

tumor mutational burden

TME

tumor microenvironment

TSAs

tumor specific antigens

WTP

willingness‐to‐pay

γδ

gamma‐delta cells

1. INTRODUCTION

Cell and gene therapies (C&GTs), also known as advanced therapy medicinal products (ATMPs), have emerged onto the clinical landscape of oncology treatments offering durable remissions and even cures for subsets of patients with hematologic malignancies and to a lesser extent for solid tumors. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ Autologous TIL, chimeric antigen receptor T cells (CAR‐T), and T‐cell receptor (TCR) cell therapies exemplify the promise of personalized immune therapies. Since 2017, the Food and Drug Administration (FDA) has approved multiple autologous C&GTs, and dozens more are in late‐stage pipelines globally. ¹⁰

Scientific success, however, has not translated into sustainable patient access or financial viability for the biopharma manufacturer, patient, or insurer willingness‐to‐pay (WTP). ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ The current centralized manufacturing commercial asset model for C&GTs, built on the biopharma “drug‐product” paradigm, has produced many systemic challenges. ¹⁸ , ¹⁹ , ²⁰ Centralized drug‐product C&GT models have led to unsustainable costs according to economic data on market failures, including bankruptcies. ¹⁸ , ²¹ In contrast, point‐of‐care (PoC) approaches have lowered costs across the globe in alignment with WTP thresholds ²² , ²³ , ²⁴ , ²⁵ and WTP evidence from a number of countries, including Asia‐Pacific, ²³ , ²⁴ , ²⁶ , ²⁷ , ²⁸ the United Kingdom, ²⁹ , ³⁰ Spain, ³¹ and China. ²¹ , ²⁷ High list prices, logistical bottlenecks, and financial fragility underscore the need for alternative delivery frameworks. This review synthesizes concepts from FDA guidance, international regulatory, financial constraints, and patient access and affordability to examine the paradigm shift toward decentralized or distributed point‐of‐care (PoC) cell manufacturing as a professional medical service instead of a commercial drug product. We also introduce the first community‐based PoC manufacturing facility in the United States as a novel and potentially disruptive use case for autologous adaptive immune cellular therapy (AAICT) for solid tumors. We conclude that reframing the C&GT delivery system from a drug‐product to a professional‐service model is critical to achieving sustainable, equitable access to personalized immunotherapies.

1.1. Novel technologies enabling PoC manufacturing

Over the past decade, many new table‐top devices and technologies have been developed to enable PoC autologous cell manufacturing. Such devices have been recently compared ³² and coined “GMP in a box.” ³³ These “all‐in‐one” “vein‐to‐vein” GMP grade devices can produce single batch autologous products for clinical trials. ³⁴ Additional technologies include aseptic connection and fluid management to keep manufacturing systems closed for aseptic processing. ³⁵ Recent advancements in rapid microbial testing methods (RMTM) such as sterility testing for bacteria, ³⁶ endotoxin, ³⁷ and mycoplasma ³⁸ are being adopted for faster product release and safety. Prefabricated clean rooms can be custom designed and installed for outpatient clinical settings ³⁹ and less expensive clear soft‐wall cleanroom containments may enable modular flexible designs. ⁴⁰ See Figure 1 for examples of devices enabling PoC manufacturing.

FIGURE 1.

Examples of devices enabling point‐of‐care (PoC) cell manufacturing. On the left are pheresis devices, and on the right are (top to bottom) rows of manual, semiautomated, and fully automated cell processing devices.

1.2. Historical FDA regulatory framework for C&GT

The US FDA historically regulated tissues and cells differently than a therapeutic biologic drug or cell therapy under Public Health Service (PHS) Act and 21 Code Federal Regulations (CFR) Part 1271. ⁴¹ For example, an autologous CD34+ hematopoietic stem cell transplant (HPSCT) is regulated as human cells, tissues, or cellular or tissue‐based products, known as “361 human cells, tissues, or cellular or tissue‐based products (HCT/Ps)” with less oversight. Whereas tumor‐infiltrating lymphocyte (TILs) cell products are regulated as a “351 biologic product” with more rigorous requirements. ⁴¹ Autologous CD34+ HPSCT is considered a 361 HCT/P because it is minimally manipulated, homologous use, autologous setting, whereas TIL and other engineered/expanded immune cell therapies (ICTs) are considered 351 biologics due to more‐than‐minimal manipulation and nonhomologous, systemic therapeutic intent. See Table 1 for comparisons.

TABLE 1.

Brief description of cell therapy type and regulatory path (U.S. Food and Drug Administration [US FDA]) for hematopoietic stem cell transplantation (HPSCT), tumor infiltrating lymphocyte (TIL), and chimeric antigen receptor T cells (CAR‐T) cells.

Therapy type	Example use	Manipulation level	Homologous use?	Systemic effect (and exemption applicability)	FDA classification	Regulatory path
Autologous CD34+ stem cell transplant (HPSCT)	Reinfusion after high‐dose chemotherapy to restore hematopoiesis	Minimal: mobilization, apheresis, enrichment, cryopreservation	Yes: restoring hematopoiesis is the same primary function	Yes, systemic effect, but exempt under 1271.10(a) (4)(ii) (autologous use)	361 HCT/P	No IND/BLA; regulated as transplant under 21 CFR 1271
TIL therapy	Expanded TILs reinfused to attack melanoma or solid tumors	More than minimal: ex vivo expansion, activation with interleukin‐2 (IL‐2)	No: expanded TILs used to treat cancer, not to restore native lymphocyte homeostasis	Yes, systemic effect without exemption	351 biological products	Requires IND then BLA; regulated as a biological product/drug
CAR‐T cells	Autologous T cells engineered to express CAR, treat B‐cell malignancies	More than minimal: genetic engineering, expansion	No: new receptor gives nonhomologous function	Yes, systemic effect without exemption	351 biological products	IND/BLA; full cGMP, comparability, potency assays

Abbreviations: BLA, biologics license approval; CFR, Code Federal Regulations; cGMP, current good manufacturing practice; HCT/P, human cells, tissues, or cellular or tissue‐based products; IND, investigational new drug.

In evaluating minimal manipulation, FDA considers the processing of the product and evaluates the extent of steps involved in transforming the HCT/P from donor specimen to finished product. In evaluating homologous use, FDA considers the way the product is marketed for its stated intent. In particular, the focus here is whether the HCT/P's intended use is to “perform the same basic function or functions in the recipient as in the donor.” ⁴¹ For this step, FDA considers the manufacturer's objective intent, as determined by product labeling, advertising, expressions of the manufacturer's representatives, and circumstances surrounding distribution. Interestingly, in a 1998 US Federal Register of proposed rules, the FDA has also explicitly left this area open for innovation, stating that “subsequent accumulation of clinical data and experience about a particular process may demonstrate that it does not alter the original relevant characteristics of the cells or tissue” may change the agency's assessment for future reconsideration. ⁴² There is FDA precedent for reclassification of minimal manipulation and homologous use, as it did in 1997 for demineralized bone products (DMB) to reclassify its initial regulation as a 351 biologic into a 361 HCT/P after urging from the American Association of Tissue Banks (AATB). ⁴² Since 1998, the cumulative number of published peer reviewed medical manuscripts cited in the National Library of Medicine “PubMed” query search term “immune cell therapy” has exponentially increased to 224,549. ⁴³ A non‐genetically modified (non‐GM) endogenous immune cell (selected or unselected) such as TIL, circulating tumor reactive lymphocytes (CTRL), natural killer (NK) cells, gamma‐delta (γδ) cells, monocyte derived dendritic cells (moDC), naïve lymphocytes, circulating tumor cells (CTCs) as antigen source for ex vivo antigen presentation and B‐cell plasmablasts (BCPB) are intended for homologous use as effector cell immunotherapy for cancer patients. We advocate here that autologous non‐GM endogenous immune cells selected, activated, and culture expanded for homologous use, ideally should be regulated by the FDA as a 361 HCT/P tissue within a cell processing FDA registered blood establishment instead of a 351 biologic drug needing an investigational new drug (IND), especially noting that non‐GM ICTs have accumulated three decades of clinical data and experience, thus necessitating less rigorous FDA oversight.

In 2022, the FDA Center for Drug Evaluation and Research (CDER) released a discussion paper “Distributed Manufacturing and PoC Manufacturing of Drugs” to identify areas for consideration as the FDA reevaluates its existing risk‐based regulatory framework. ⁴⁴ The FDA discussion paper introduced PoC manufacturing scenarios along with multiple clarifying definitions as a potential prelude to future FDA reassessments of fault line regulatory reclassifications of 351 versus 361 HCT/P. Figure 2 provides a summary outline to describe three elements of the FDA white paper as follows. The manufacturing unit (MU) used in distributed manufacturing (DM) is often a mobile MU, such as nonpermanent MUs colocated at a health care facility (HCF). Key responsibilities of the IND applicant include the central pharmaceutical quality system (PQS) oversight of all sites, tracking the MUs, compliance with GMP requirements, and alternative scenarios such as ancillary production by contract drug manufacturing organization(s) (CDMO). The manufacturing platform (MP) is described from production inputs, data systems, assays, and quality assurance including quality control to demonstrate chemistry, manufacturing, and controls (CMC) concordance with each MU, DM unit, and location.

FIGURE 2.

U.S. Food and Drug Administration (FDA) discussion paper on point‐of‐care (PoC) manufacturing scenarios.

The FDA PoC discussion paper evaluated the framework for distributed, decentralized, and PoC manufacturing with additional insights from the Regulatory Affairs Professionals Society (RAPS) news release in 2023 ⁴⁵ and public workshop in 2022 with stakeholder feedback to provide guidance on this approach. However, US sponsors still face hurdles of IND, biologics license approval (BLA), site GMP, and comparability issues causing PoC manufacture to be unfeasible at scale today in the United States.

The prior FDA draft guidance for C&GT CMC changes and comparability was released in 2023. ⁴⁶ Recently in January 2026, the FDA released information about new flexibility on requirements for C&GT CMC to advance innovation and expedite product development with the rapid pace of scientific advancements. ⁴⁷ Although not yet a formal guidance paper, this FDA information described general flexibilities in three categories: clinical development, commercial specifications, and process validation. During phase 1 clinical trials, the FDA will not expect compliance with 21 CFR 210.2c, enabling less strict compliance for GMP regulations for early lifecycle refinement of process and method validations, including minor manufacturing changes without pre‐change and post‐change onerous comparability data, with permissive product quality release acceptance criteria. For commercial specifications, the FDA will consider flexibility in product release criteria that are appropriate for the product's complexity and development maturity. This may apply to reevaluating release criteria based on post‐approval manufacturing experience with data supporting consistent product quality. In regard to process validation flexibilities, there is a recognized need for concurrent distribution of specific process performance qualification (PPQ) lots on a batch basis followed by completion of protocol execution steps. The number of PPQ lots for process validation is not stipulated or required to be three (3). As a result, during review by FDA, the appropriate number of lots will be considered in the context of the overall process.

1.3. International regulatory frameworks enabling PoC cell manufacturing

UK's Medicines and Health Care Products Regulatory Agency (MHRA) recent 2025 “Human Medicines and PoC Regulations” are the only codified, license‐level blueprint that explicitly enables modular manufacturing (MM) at the PoC using a “modular unit” as defined by MHRA as a “relocatable manufacturing unit.” ⁴⁸ The UK MHRA PoC “modular unit” is analogous to the US FDA PoC discussion paper description of “manufacturing units” defined by the FDA as a mobile manufacturing process, including equipment, peripheral, and interfaces that may be part of a MP. The UK MHRA regulations describe a common structure for a broadened spectrum of manufacturing and supply options, including mobile (i.e., bus), PoC (i.e., HCF), and/or at home as a “virtual ward.” The MM or PoC common structure is based on a control site “hub” (supervises and controls the product) and “spoke” (PoC/MM process and site) model under the manufacturer's license with a “master file” that details the approved licensed process. ⁴⁹ We advocate for the US FDA to make changes to enable PoC manufacturing similar to United Kingdom's PoC regulations. ⁴⁸

The European Medicines Agency (EMA) offers Hospital Exemption (HE), which eases patient‐specific in‐hospital use but does not create a PoC manufacturing license akin to the United Kingdom. ⁵⁰ Asia–Pacific shows fast‐access models in Japan, ⁵¹ , ⁵² China ⁵³ and Korea ⁵¹ and fit‐for‐purpose frameworks in Singapore. ⁵⁴ Australia is actively refining rules, including a specific workstream on PoC device manufacture, ⁵⁵ but none yet mirror the United Kingdom's formal control‐site and master‐file approach. ⁴⁵ Figure 3 provides a global landscape of the aforementioned PoC cell therapy manufacturing regulations focusing on selected regulatory agencies, status and start date, products, and PoC‐friendliness.

FIGURE 3.

Global landscape comparing selected regulatory agencies status, products, and point‐of‐care (PoC)‐friendliness of cell therapy regulatory frameworks.

1.4. International PoC manufacturing is outpacing United States

International experience demonstrates that alternative delivery models are both feasible and more sustainable. Spain's hospital‐manufactured CAR‐T therapies under the HE, ^{31 56} China's domestically priced CAR‐T products with outcomes value based contracts. ⁵⁷ Japan's capped co‐payment system ⁹ is a high‐cost medical expense cap that functions as a monthly out of pocket maximum that sits on top of Japan's standard coinsurance if a patient's monthly cost sharing exceeds an income/age‐dependent ceiling. ⁵⁸ This enables Japan to cover expensive one‐time C&GT while still limiting what an individual patient pays out of pocket in a given month. ⁵⁹ These global PoC delivery system models show that autologous cellular immunotherapies can be “democratized” and delivered at price points more consistent with patient and societal WTP. The United Kingdom's statutory framework for PoC manufacturing provides the clearest regulatory blueprint for reframing C&GT delivery as a professional‐service paradigm rather than a commercial drug product. ⁴⁸ , ⁶⁰

1.5. Cell therapy accreditations enabling PoC manufacturing

HCFs planning PoC manufacturing will need regulatory compliance within their region's regulatory agency such as the FDA, EMA, or MHRA. Furthermore, HCFs will need independent accreditation to demonstrate quality and safety in practice. Foundation of the Accreditation of Cellular Therapy (FACT) is US‐based, jointly established by the International Society for Cell and Gene Therapy (ISCT) and American Society for Transplantation and Cellular Therapy (ASTCT) and historically accredits inpatient programs such as bone marrow transplantation. Joint Accreditation Committee ISCT‐Europe (JACIE) and European Bone Marrow Transplant Organization (EBMT) is the European counterpart to FACT as harmonized and jointly published, covering HPSCT, immune effector cell therapy (CAR‐T, TILs, NK, etc.), cord blood banking, and cellular processing labs. The Association for the Advancement of Blood & Biotherapies (AABB) is US‐based and offers cellular therapy product services accreditation which covers collection, processing, storage, and administration of cellular therapy products. AABB is recognized internationally (over 50 countries) and historically accredits outpatient clinical services such as blood banks, transfusion services, and cord blood programs but increasingly covers cell therapy labs. A brief comparison of FACT & AABB accreditations is shown in Figure 4.

FIGURE 4.

Comparison of Foundation of the Accreditation of Cellular Therapy (FACT) and Association for the Advancement of Blood & Biotherapies (AABB) accreditation.

1.6. First US community based PoC manufacturing facility: Novel use case to enable autologous adaptive immune cell therapy

1.6.1. Innovation and impact

The National Cancer Institute (NCI) estimated that there were 18M cancer survivors in the United States in 2022, with the cost (NCI estimate) of care and drugs to be $208.9B in 2020. ⁶¹ The aging population prevalence trajectory has been described as an upcoming “silver tsunami” of cancer survivors. ⁶² The recent COVID pandemic resulted in a large portion of patients missing or delaying cancer screenings, resulting in a recent “stage migration” to more advanced metastatic stages of cancers at initial presentation. ⁶³ With the rising prevalence and stage migration of metastatic cancers, there is a critical need for promising AAICT to reach into community‐based settings through an affordable and accessible delivery model.

A warm‐chain PoC manufacturing enables the sourcing of the autologous cells, manufacturing of the effector cell product and reinfusion of the product in a “warm chain,” without freezing or refrigerating the products. The adjoining proximity of leukapheresis (LKA), GMP clean room suites, and a phase 1 clinic at the PoC enable immediate coordinated transfer of fresh cells without any logistical delays, thus a “warm chain.” Herein, we present a novel PoC warm‐chain delivery model of AAICT that could be paradigm shifting, with an individualized treatment modality to be delivered at a vertically integrated human applications laboratory (HAL). ⁶⁴ BioCytics was founded in 2005 in Huntersville NC for research and development of autologous ICTs at its GMP cell processing facility (CPF) adjacent to a phase 1 research clinic. See Figure S1, for a list of core capabilities enabling a vertically integrated PoC cell therapy center. Encompassing all operational activities is an essential commitment to quality through integral quality management system(s) (QMS) of document control, quality assurance (QA), quality control (QC), accreditation activities, and licensure. These technical capabilities include a robust translational laboratory research services team highly trained in good laboratory practice (GLP) studies to enable an individualized cell therapy pipeline for clinical trial patients. While CDMOs have traditionally been responsible for manufacturing clinical trial investigational products, PoC manufacturing can accomplish this by achieving GMP‐compliant processes including oversight by a dedicated quality unit (QU), also referred to as quality control unit, to ensure QA and QC. The QU is responsible (along with executive management) and authorized for ensuring compliance with GMP regulations including approval or rejection of all materials, processes, recordkeeping, standard operating procedure(s) (SOP)s, assays, quality control, environmental monitoring, validations, and verifying production was error free (or fully investigated) prior to release of production batches. Furthermore, adequate facilities are required to be GMP‐compliant along with appropriate personnel qualifications. The clinical diagnostics laboratory and biobank are available to support patient testing and biospecimen banking respectively. LKA capabilities require highly skilled medical professionals along with properly maintained pheresis equipment. Leveraging decades of experience enables the institute to function in a contract research organization (CRO) capacity to support internal and external clinical trial programs. BioCytics Digitally Integrated Clinical Enterprise (BioDICE) solves the problem of digital integration from numerous data sources, procedures and healthcare information. This PoC AAICT is an innovative adaptation of a DM platform capable of generating effector cell fractions against solid tumors, and potentially applicable to many other chronic diseases. This approach has the potential to reduce costs while expanding patient access.

1.7. PoC facility design and integrated infrastructure

BioCytics' affiliate, Carolina BioOncology Institute, PLLC (CBOI) is colocated with BioCytics' current good manufacturing practices (cGMP) facility. BioCytics' HAL is a CPF design adapted from cGMP clean room design layouts. ⁶⁵ This model by James (2017) maximizes automation by untethering incubation from automated processing, thus quadrupling clean room production output while decreasing the incubation footprint. ⁶⁵ BioCytics single batch autologous “point of care” manufacturing maximizes a “large ballroom” modular facility for closed automated systems with centralized incubation, parallel processing, high utilization of equipment, and facility with minimal labor and freedom to move. The current 31,000 sq.ft. clinic and HAL facility was designed to enable a capacity of 2000 (per year) patient LKA and corresponding autologous patient products manufactured products with only 13 production staff, 7 automated closed processing systems with centralized incubation in a 200 m² (~2150 sq.ft.) clean room and clinical trial infusion room doses per year. ⁶⁴ Currently, five BioCytics GMP clean rooms have a total combined 3820 sq.ft. including anterooms and corridors which have the capacity to exceed the James (2017) model with a similar facility design. Scheduling 2000 LKA collections per year equates to 8 patients per day, Monday–Friday, which could be readily accomplished with 4 LKA chairs (each chair assigned a morning & afternoon patient) and 2 nurses concurrently supervising LKA. A large monitored infusion room shared for LKA and patient infusion dosing enables maximal flexibility to utilize LKA chairs as infusion dosing chairs interchangeably. A single LKA collection product can be “fractionated” into multiple different immune effector products for downstream parallel processing then moved into dedicated incubator space. Autologous fractions may be selected (or subselected) serially using the same device and then placed into separate flasks for incubation. In the coming years, the CBOI‐BioCytics facility plans to expand its current footprint into adjacent suites totaling 60,000 sq.ft. (occupying our entire building) of which its capacity may double the patient referrals and autologous products per year. CBOI‐BioCytics goals are to provide an option for the 20,000 North Carolina stage IV solid tumor cancer patients within driving distance with access to enroll in clinical trials with AAICT. ⁶¹ CBOI‐BioCytics PoC efficiencies are based on cross‐training roles in a customized purpose‐built integrated facility by design. CBOI's oncology certified nurses (OCNs) are cross‐trained as research nurses for immuno‐oncology (IO), infusion room, symptom management, regulated phase 1 trial cGCP management, and AABB LKA GMP collection. BioCytics laboratory staff are cross‐trained in high‐complexity clinical laboratory improvement amendments (CLIA) diagnostic “stat lab,” LKA peripheral blood mononuclear cell (PBMC) effector cell processing, GLP translational research including flow cytometry, tumor culture, and cGMP manufacturing in clean rooms. These clinical and laboratory cross‐training duties enable a dynamically integrated team to perform the broad spectrum of tasks needed in a good clinical practice (GCP)‐CLIA‐GLP‐GMP regulated environment with 589 SOPs and work‐aids currently in our document controlled QMS.

1.8. PoC digital integration and software development

The BioDICE system will provide a fully interconnected bioinformatics platform to manage the complete process flow of oncology immunotherapy clinical trials, merging the functionality of an EMR (electronic medical record system), EDC (electronic data capture system), CTMS (clinical trial management system), HALIMS (human applications laboratory information management system) under a unified data model, and user interface, to support clinical trials across the public health landscape. BioDICE platform is based on international recognized health data standards: health level seven (HL7) Fast Healthcare Interoperability Resources (FHIR) for ingestion of health system interoperability data, Open Electronic Health Records (openEHR) for clinical data structure, persistence, and patient sovereignty, Logical Observation Identifier Names and Codes (LOINC) for laboratory and medical device integration, International Classification of Diseases (ICD) for disease classification, Systematized Nomenclature of Medicine (SNOMED) for medical dictionary terminology, Clinical Data Interchange Standards Consortium (CDISC) for clinical research trial data capture and analysis, Medical Dictionary of Regulatory Activities (MedDRA) for regulatory authority activities and submission, International Council of Harmonization, Multidisciplinary 11 Template, Clinical Electronic Structured Harmonized Protocol (ICH M11 CeSHarP) for clinical trial embedding into EMRs and International Organization for Standardization (ISO) for international best practices for infrastructure of highly reliable organizations. BioDICE software is being developed in Microsoft Azure so that AI machine learning may enable feedback algorithms from clinical data, laboratory “omics,” and in‐line manufacturing critical quality attributes (i.e., immune cell–tumor coculture cytotoxicity assays) for rapid iteration of individualized cell therapies to recapture tumor escape based on the real‐time data monitoring. BioDICE software demonstration was recently presented at the openEHR annual symposium EHRCON 2025 in Barcelona Spain and is based upon the recent manuscript “Converge or Collide? Making Sense of a Plethora of Open Data Standards in Health Care” authored by the leadership of HL7, openEHR and Observational Health Data Sciences and Informatics (OHDSI). ⁶⁶ An overview of BioDICE is shown in Figure 5, and the video presentation may be viewed on the openEHR YouTube channel. ⁶⁷

FIGURE 5.

Schematic perspective of BioCytics Digitally Integrated Clinical Enterprise (BioDICE). A digital health platform to embed cancer research trials into Open Electronic Health Records (openEHR) for electronic data capture system (EDC) to develop personalized medicines manufactured at the point‐of‐care (PoC).

1.9. PoC manufacturing platform

CBOI‐BioCytics infrastructure forms a fully integrated warm‐chain PoC MP where a patient's immune cells can be collected by blood draw or LKA, immediately transferred to the adjacent GMP‐compliant HAL for AAICT manufacturing over 10–14 days, and followed by harvest for same‐day dosing to the patient. This MP is key to the production of autologous nongenetically modified cells with the highest specificity and functionality. ⁶⁸ AAICT therapies are generated from PBMC‐derived immune cell lineages of multiple “fractions” that are selected for their abilities to identify and target cancer cells in an adaptive and synergistic manner. Cell selection is based on phenotype and performed using magnetic selection or flow‐assisted cell sorting. These methods are currently used in many clinical trials, and the FDA CBER (Center for Biologics Regulation and Evaluation) has a Master Files (MFs) database used in C&GT manufacturing which IND applicants may reference (such as media, reagents or devices) if the MF holder authorizes as suitable for clinical trial use. ⁶⁹ Rather than using genetically modified CAR‐T, AAICT immune cell fractions can target cancer cells by specifically recognizing neoantigens, phosphoantigens, oncofetal proteins, innate signals of tumor cellular stress markers, epithelial mesenchymal transition (EMT), or downregulation of human leukocyte antigen (HLA) that are individually specific to each patient's tumor burden and immune fraction (discussed in following section). This approach is achievable through a vertically integrated warm‐chain PoC manufacturing AAICT platform as it overcomes the logistical limitations of conventional manufacturing. BioCytics‐CBOI integrated delivery model enables AAICT to be researched and developed on an IRB approved clinical trial, while being accessible and affordably delivered for the highest efficacy and safety.

As shown in Figure 6, warm‐chain manufacturing workflow for future clinical trials of metabolically fit, individualized cell fractions expanded to stoichiometrically therapeutic‐range clinical doses intended to circulate and transmigrate into the tumor microenvironment (TME) to efficiently kill tumor cells, as either a monotherapy or in combination. This includes a pipeline of multiple fractions of ICTs, manufactured without the need for freeze–thaw steps, directly resulting in increased cell viability, count, and functionality at a reduced “needle‐to‐needle” delivery time and reduced costs compared to traditional centralized manufacturing. This futuristic warm‐chain PoC AAICT clinical approach using multiple cellular fractions, in combination with longitudinal iterations, has not yet been fully tested or attempted by any academic institution or biotech company for several reasons, including the high barrier to entry of PoC “bespoke” manufacturing and the legacy of traditional centralized manufacturing conventions for “single dose” cellular immunotherapies. ⁷⁰

FIGURE 6.

(A) contemporary industry workflow for immune cell therapy (ICT) involves 14+ individual process steps that require freeze–thaw cycles and complex logistical operations. (B) An ideal novel warm‐chain point‐of‐care (PoC) process potentially reduces logistics and associated costs by more than 50% and eliminates freeze–thaw for faster readiness of cellular therapy at higher viability.

1.10. Immunotherapy fractions

Cancer immunotherapies rely upon a functional host immune system; however, the cancer patients' immune system is often dysfunctional from exhaustion as defined by loss of metabolic fitness to target and kill cancer. ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶ Cancer patients' immune system may also be anergic with primary immune resistance as a state of unresponsiveness or tolerance, even in the presence of recognized antigens such as reexpressed oncofetal antigens. Cancer patients' immunological tolerance to “public” tumor‐associated antigens (TAAs) quiesce autoimmunity while limiting anticancer immune response because TAAs are also expressed in normal tissues. Furthermore, cancer patients treated with chemotherapy develop chronic lymphopenia adversely impacting lymphoproliferation to autonomously fight cancer. Immunogenic “private” neoantigens, also referred to as tumor specific antigens (TSAs), are constantly changing from mutagenic drift, thus requiring a novel strategic approach to overcome tumor acquired “secondary” immune resistance ⁷⁷ to recapture “tumor escape.” All of these cancer patients' immune disadvantages signify the unmet clinical need for ex vivo immune cell manufacturing to overcome primary and acquired secondary immune resistance.

Warm‐chain PoC manufactured AAICTs involve carefully selected immune cell fractions. Manufactured autologous immune cells persist in the host, thus circumventing the risk of allogeneic donor rejection. ⁷⁸ , ⁷⁹ Lower manufacturing costs and shorter turnaround time for critically ill patients seeking treatment are also benefits. The first BioCytics immune fraction (BCyIF1) to be manufactured is an exhausted‐reinvigorated T‐cell fraction, is antigen experienced, thus exquisitely specific and reactive to the autologous tumor. Reinvigoration of exhausted cells can occur without genetic modifications or induced pluripotent stem cell (iPSC) reprogramming. If approved by FDA for an IND phase 1a trial in 2026–2027, we anticipate outpatient tolerability with reduced off‐target effects since BCyIF1 retains its natural intrinsic immune inhibitory modulation mechanisms, and because BCyIF1 lacks genetic modifications that would induce sustained proliferation. Additionally, we are developing a broad pipeline of other AAICT fractions (see Figure 7) that are synergistic for solid tumors, including a memory natural killer (mNK) cell fraction (BCyIF2) and a Gamma‐Delta (γδ) T‐Cell fraction (BCyIF3), surgically resected tumor‐infiltrating immune cells (TIIC) (BCyIF4) and ex‐cellerator lymph node (Ex‐CLN) (BCyIF5). These fractions, both immune type and specific phenotype, can be isolated from tissue samples, blood or LKA using immunomagnetic selection or flow‐assisted cell sorting. The metabolic fitness and sequential TME penetration of these subpopulations are manufactured to resemble the natural orchestration of an anticancer immune cell influx, and to be synergistic with cancer checkpoint drug immunotherapies. We envision AAICT fractions may be recollected and reinfused sequentially or in combination based on tumor burden, response or escape kinetics. Future Phase Ib cohorts of AAICT are compatible with combinations with checkpoint drugs that can be chosen based on the AAICT phenotypic characteristics or shifting tumor biology.

FIGURE 7.

BioCytics autologous adaptive immune cellular therapy (AAICT) as multiple immune cell fractions derived from tumor resection, leukapheresis (LKA), or whole blood (WB) which may be used as monotherapy, sequential, or combined reiteratively adaptive based upon clinicopathologic feedback algorithms including biomarkers and functional circulating tumor cell (CTC)‐immune killing assays.

1.11. Novel ex vivo immune‐engineering: Pre‐thymic derived lymphocytes for ex‐vivo antigen presentation to overcome tumor self‐tolerance

Although mutation‐derived TSAs such as neoantigens can be highly immunogenic (“hot tumor”), they represent a minority of expressed tumor antigens, often referred to as “private antigens.” High tumor mutational burden (TMB) cancers defined as >10 mutations per megabase sequence comprise only 14% of all solid tumors, which are also the tumors most likely to respond to immune checkpoint blockade (ICB). ⁸⁰ A “cold tumor,” poorly immunogenic, with low TMB without host immune recognition is considered “ignorant” of its' shared self‐derived TAA, as is often manifested by primary resistance to ICB. ⁸⁰ Low mutational burden tumors with nonmutated shared self‐derived TAAs include overly or aberrantly expressed antigens such as MUC‐1, MART‐1, Her‐2, NY‐ESO‐1, MAGE‐A, including other cancer‐testis‐antigens, amplified oncogenes, or oncofetal antigens. Nonmutated shared self‐derived TAAs are the most common antigens on most solid tumors, often referred to as “public antigens,” but are also present in normal tissues. ⁸¹ , ⁸² These shared self‐derived TAAs are subject to central tolerance due to thymic negative selection; therefore, an engineered ex vivo prethymic lymphoid‐derived strategy would have the potential to unlock higher‐avidity broader TCR repertoire recognition of these shared self‐derived TAAs. Strategies that expand or regenerate lymphocyte repertoires with reduced tolerance constraints may preferentially enhance recognition of shared self‐derived TAAs and facilitate downstream immune response with epitope spreading.

It is known that 95%–97% of “thymocytes” (lymphatic precursors) undergo null selection due to lack of self MHC binding, or negative selection due to auto‐reactivity in the thymus. The remaining surviving 3%–5% of positively selected lymphocytes are released into the periphery as mature naïve T‐lymphocytes to encounter future antigens. ⁸³ Recent quantification studies on the thymic selection of TCR repertoire have been performed in transgenic mouse models with reporter markers by tracking and sorting thymocytes throughout early development and comparing to mature lymphocytes in the spleen ⁸⁴ Their results supported the hypothesis that thymic selection imposes a “weak selective pressure on the TCR repertoire” of which a subtle selection shift may translate into a “robust self/nonself discrimination” of auto‐reactive TCRs. This would be manifested downstream in an immune response if a “quorum sensing mechanism between multiple clonotype TCRs occurs via cytokine signaling.” Other authors have estimated a minimum quorum size of 30 activated T cells of different TCR repertoires for “collective induction” of T‐cell memory. ⁸⁵ These studies suggest that a small fractional increase in the release of prethymic lymphocytes (without negative selection of self auto‐reactivity) could potentially surpass the minimum quorum of activated lymphocytes to induce an auto‐reactive shared self‐derived TAA response to overcome self‐tolerance of a tumor.

Circulating naïve T cells lack the capacity to mutate their TCR genes after intra‐thymic selection, unlike B‐cell receptors, which do have additional combinatorial diversity of V(D)J recombination with functional avidity maturation. However, “prethymic” naïve lymphocytes that have not undergone negative “self” selection in the thymus can be collected and enriched from rare LKA‐derived CD34+ hematopoietic stem progenitor cells (HSPCs) to be engineered into naïve T cells of significantly higher diversity potential for a more robust antitumor response to overcome self‐tolerance of a tumor. We hypothesize that metastatic cancer patients with primary refractory resistance to ICBs could potentially benefit from CD34+ HSPCs selected and differentiated into prethymic lymphocytes, educated by ex vivo TAA antigen presentation resulting in a more diverse TAA targeted TCR repertoire for infusion. This approach could theoretically convert a cold tumor into a hot tumor by “shared self‐derived TAA epitope spreading.”

In 2017, the first generation of T cells derived from CD34+ HSPCs using artificial thymic organoids (ATO) to recapitulate full span thymopoiesis (pre‐, intra, post) resulted in mature naïve phenotypes with a diverse TCR. ⁸⁶ The ATO field is rapidly advancing with the goals to overcome self‐tolerance with engineered CD8 cell for cancer immunotherapy or induce CD4 Treg tolerance in rheumatologic disease. ⁸⁷

BioCytics' most dynamic, de novo, and patient‐tumor specific AAICT fraction in development is the Ex‐CLN, also referred to as BCyIF‐5, which begins with selected CD34+ HSPCs differentiated into prethymic naïve lymphocytes. BCyIF‐5 HSPCs will be differentiated into lymphoid ontogeny lineages of αβ T cells, γδ T cells, and B cells to leverage prethymic somatic recombination potential to generate TCRs targeting shared self‐derived TAAs. Ex‐CLN is based upon the premise that most solid tumors reexpress shared self‐derived TAAs. Central tolerance imposes a self‐constrained immune repertoire by deleting high‐affinity self‐reactive TCR clones during development, thereby limiting which antigen specificities are available to the host. We predict BCyIF‐5 engineered ex vivo CD34+ HSPCs pre‐thymic lymphocyte would have an exponentially greater combinatorial diversity of V(D)J recombination with functional avidity maturation through selection and cellular tuning against shared self‐derived TAAs, as compared to an endogenous post‐thymic lymphocyte pool constrained by self‐tolerance. Albeit the significant risk of also inducing autoimmune toxicities, thus should only be attempted in the context of an IND approved phase 1 cancer clinical trial with a team experienced in managing autoimmune adverse events. Consideration of a CD34 engineered construct “suicide switch” or inducible promoter dependency on an exogenous drug could rescue and abort immune toxicity. ⁷⁷

2. DISCUSSION: KEY STRATEGIES FOR PoC AAICT IMPLEMENTATION

2.1. Clinical trial design strategy

AAICT has potential broad therapeutic clinical utility but presents many unique challenges. Immune cells originate from the patient are delivered to the same patient, and must be longitudinally adapted to tumor evolution. Therefore, AAICT is being initially developed with intent for repeating LKA for serial batch manufacturing of iterations of BCyIF1 to recapture tumor escape of shifting antigen repertoire if patients develop secondary immune resistance. Future separate INDs of BCyIF2, BCyIF3, and BCyIF5 will incorporate combinations of multiple IND fractions on a master protocol designed as a Bayesian adaptive platform trial with enrichment, matching, and feedback algorithms with cross‐over arms based on clinical responses, CTC biomarkers, and cellular manufacturing coculture tumor killing assays. ⁸⁸ We envision future treatment protocols will be guided by a proprietary, machine learning feedback algorithm allowing each iteration to recapitulate the actual tumor antigen repertoire at the time of cell isolation based on CTCs. While these products are only in early development and mostly conceptual, we anticipate that it will be possible for these fractions to operate synergistically to impact primary and secondary immune resistance by recapitulating the natural immune process of an innate immune response followed by an adaptative response. Additionally, the accessibility to maximally fit immune fractions could also be a benefit to patients in the minimal residual disease (MRD) or adjuvant setting.

2.2. Strategically recapturing tumor escape: LKA derived CTCs to chase the antigen source of a shifting target

As their name suggests, CTCs are cells that have detached from a tumor and are now circulating through the bloodstream. ⁸⁹ While rare, CTCs can be identified and isolated from a patient's blood. ⁹⁰ , ⁹¹ , ⁹² , ⁹³ Because they come from the patient's actual tumor, CTCs provide a source for studying the patient's tumor cells without requiring an invasive biopsy procedure. ⁹⁴ The insight provided by CTCs can be informative for cancer diagnosis and prognosis, and may provide predictive clues about functional immune fraction cytotoxicity assays to predict the best tumor killing fraction. CTCs may also provide cancer‐specific neoantigens to “activate and reeducate” the immune fractions for expansion and future dosing, intending to longitudinally recapture tumor escape.

We envision AAICT future combinatorial sequence feedback algorithms with machine learning capabilities will select the best immune fractions based on coculture immune tumor killing assays for each patient, thus recapitulating an orderly orchestration of fractions that mimics natural immune recognition. ⁹⁵ For example, first the innate‐type immune cells would theoretically display the most effective initial tumor infiltration, followed by adaptive immune cells for neoantigen specific response. This type of functional tumor‐immune assay feedback will allow us to adapt to cancer changes over time, reinforcing durable immune responses. Iteratively manufactured doses of AAICT can be freshly generated within 2 weeks from a simple blood draw or LKA using our warm‐chain structure. AAICT feedback algorithms, based on patient specificity, CTC antigen repertoire, cytotoxic mode of action, and EMT phenotype, allow for iteration of immune cell fractions in a synchronized, sequential or parallel fashion to recapture tumor cells that have been able to escape the immune system.

BioCytics 0001 initial laboratory‐based clinical trial titled “A Biospecimen Collection Study of Leukapheresis‐Derived CTCs, Immune Cells, and Progenitor Cells” opened in 2007 and has accrued 1197 patients (at the time of this manuscript) for whole blood research and tumor biopsy collections and serial CTC collections. ⁹⁶ This BioCytics 0001 trial has also enabled collection of viable “matched pairs” of immune cells and tumor cells for coculture “killing assays” to perform translational research and development on multiple immune fractions to research the best reagent cocktails for effector cell activation and expansion.

BioCytics had initially published in 2012 in Frontiers in Oncology about the concept of LKA derived viable CTCs as the “substrate of personalized medicine” ⁸⁹ and then published in 2013 in Cancer Letters the results of differential drug responses of viable CTCs from whole blood. ⁹⁷

Since CBOI‐BioCytics' first LKA in 2016, a total of 241 consented patients on the BioCytics 0001 trial ⁹⁸ have undergone LKA to compare metastatic cancer patient immune cells to healthy volunteers and optimize LKA‐derived CTCs for selection and culture and supported our PoC model development as described in the 2021 publication in Immuno‐Oncology Insights “Driving a new model for point‐of‐care cellular cancer immunotherapy manufacturing.” ⁶⁸ Fresh LKA from this laboratory trial also enabled preclinical research and development, in vivo murine and avian studies followed by IND‐enabling optimization of BCyIF‐1, which was reviewed by the FDA for the Initial Targeted Engagement for Regulatory Advice on CBER/CDER Products (INTERACT) meeting that was granted in 2025. ⁹⁹

Multiple recent publications support the functional utility of LKA derived patient‐derived tumor organoids (PDTOs) for viable culture expansion for modeling prostate cancer and DNA sequencing ¹⁰⁰ and NSCLC for EMT axis, stemness, immune responsiveness and metabolism ¹⁰¹ and for precision immunotherapy ¹⁰² and immune cell coculture ¹⁰² , ¹⁰³ and to analyze personalized T‐cell responses to neoantigens. ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁶ PDTOs have demonstrated treatment response prediction in colorectal cancer, ¹⁰⁷ NK T‐cell based cancer immunotherapy, ¹⁰⁸ and unlock “liquid biopsy” frontier applications such as 3D bioprinting, microfluid organ‐on‐a‐chip, nanodrug studies at the intersection of precision medicine, tumor pathogenesis, and organoid immunocyte interactions. ¹⁰⁹

2.3. Warm‐chain strategy for AAICT viability and functionality

The BCyIF‐1 T‐cell fraction is highly reactive to the patient's private tumor antigen repertoire, and we have been able to demonstrate (internal data) high specificity and cytotoxicity following the reinvigoration process and expansion fold >700× (without feeder cells). The challenge with exhausted cells in a terminally differentiated state is an overall inability to proliferate and low capacity to kill cancer cells, ¹¹⁰ which also make them very sensitive to ex vivo manipulation or freezing. This can lead to loss of viability ¹¹¹ or post‐freezing loss of T‐cell interferon gamma (IFNγ) response in chronic viral studies of terminally differentiated exhausted T cells which underscores that freeze/thaw stress may induce profound loss of immune functionality such as in human immunodeficiency virus (HIV) infected individuals. ¹¹² Our internal data showed that BCyIF1 precursors are particularly sensitive, with a 20% drop in viability after freezing, and a significantly lower fold‐expansion (data not shown). Freezing ICT products (or source sample) still remains a necessity, especially for the deployment of cell therapies in remote areas, or in case of need for additional rounds of production (if the patient is not ready to receive an infusion, or if dose manufacturing fails for example). This modality has not prevented the successful deployment of CAR‐based therapies, but it remains that immune cells function can be deeply impacted by freeze–thaw cycle, especially in cells that are highly sensitive to environmental changes such as NK cells, ¹¹³ and that impact can reduce a therapy's efficacy.

The BCyIF‐2 mNK Cell fraction is an ex vivo reinvigorated, autologous memory NK cell fraction, specifically expanded for its cytotoxicity and memory‐like properties. This subpopulation originates from multiple cancer activations and is particularly robust, able to recognize cancers' downregulation of HLA “self” markers and is sensitive to multiple activation ligands such as recognizing tumor phosphoantigens. ¹¹⁴ However, it has also been shown that freezing is deleterious to NK cells by impairing their cytotoxic potential, 3D migration, and CD16 expression, ¹¹³ which makes relevant the novel application of a warm‐chain delivery within a PoC model to maximize these cells' potential therapeutic impact.

2.4. Combinatorial therapeutic strategy: Multiple fractions orchestrated synergistically

The autologous BCyIF‐3 γδ T‐cell fraction is an ex vivo reinvigorated cell fraction selected for their evolutionarily conserved ability to have the highest variable domain combinatorial diversification to recognize antigens (including phospho‐antigens) directly presented by cancer cells (especially colon cancer), independent of HLA “self” context. ¹¹⁵ , ¹¹⁶ While these fractions have the potential to work independently, combinatorial therapies that would mimic a natural response represent an intriguing solution. These therapies have shown encouraging results by combining NK and T cells to enhance tumor lysis and overcome HLA‐1 downregulation, ¹¹⁷ but the intricate nature of these therapies will be an obstacle to their clinical deployment. A PoC model with rapid cell manufacturing of each fraction has the potential to overcome these issues. Surgically resected TIIC (BCyIF4) are tumor‐experienced immune cells of multiple fraction lineages (myeloid and lymphoid), which are informative about the host's immune functional status and provide a valuable tumor antigen source. TIIC are often exhausted but can be selected, reinvigorated, and expanded as a valuable fraction. Lastly, given its prethymic nature, Ex‐CLN (BCyIF5) cells are anticipated to be highly potent yet specific with high levels of serial killing and self‐renewal capabilities.

2.5. Regulatory pathway strategy

Following immune cell fraction identification and characterization, there are a number of steps to scale up for each investigational new drug (IND) application. The first step is to optimize isolation, expansion, and reinvigoration of multiple immune cell fractions, along with development of the machine learning algorithm to determine optimal therapeutic approach. Second are in vivo studies for proof‐of‐concept of our iterative and combinatorial immune cell fraction approach and scale‐up of processes. Third, perform qualification runs, pharmacology and toxicology studies, CMC data package, engage in IND preparation including pre‐IND meetings with FDA, and complete the IND submission process, including any follow‐up work as requested by the FDA. The final stage is to initiate the BioCytics master protocol clinical trial. Recently, in November 2025, BioCytics BCyIF1 passed an FDA INTERACT meeting to support moving into Pre‐IND stage with initial regulatory derisking BioCytics PoC manufacturing model. ⁹⁹

3. SUMMARY

In 2023 CBOI‐BioCytics became the first AABB accredited independent community‐based phase 1 research cancer clinic with LKA collection and PoC GMP manufacturing capabilities in the United States. Decentralized manufacturing brings cell processing closer to the patient and improves efficiency in both time and cost for personalized cellular therapy. A vertically integrated warm‐chain PoC AAICT MP overcomes the logistical limitations of conventional manufacturing to enable the most bioactive pan‐cancer individualized immune cells to be accessible and affordably delivered to metastatic patients. Development of multiple cell fractions enables access for broader tumor types and potential for therapeutic benefit while leveraging the most efficiency from PoC MP. Each fraction will be further optimized through stepwise iterations of the best methods and reagents to isolate, expand, and reinvigorate the cells. The cell fractions will be systematically characterized in vitro (via “‐omics,” molecular, phenotypic characterization, cytotoxicity, cellular fitness studies) and in vivo (e.g., toxicity and efficacy) testing. Characterized cell fractions then move into process development optimization and upscale fractions of warm‐chain PoC manufacturing. These advancements can be performed in a parallel fashion for efficiency of reagents, time, and samples needed to complete safety, toxicology, pharmacology, and effector functions for each fraction. Combinatorial potential in terms of synergies and timing of administration can also be explored during this phase. Success of the Phase Ia trial of each IND will then enable combinatorial fractions for the Phase Ib trial, followed by upscaling the clinical trial network of the warm‐chain PoC AAICT platform.

4. CONCLUSIONS

C&GT have delivered unprecedented clinical breakthroughs in oncology, yet the centralized commercial drug‐product model has proven financially fragile and operationally inefficient. Even where therapies have gained FDA approval, commercial success has been elusive, with companies trading at a fraction of asset value and health systems struggling to reconcile prices with budgetary realities. Adopting PoC models has the potential to align innovation with health system affordability, broaden patient access, and ensure the long‐term viability of personalized immunotherapy. In the future, BioCytics warm‐chain PoC AAICT platform could potentially be applied to all solid tumors of all grades, all TMB status, and all stages including early detection and recurrence by diagnostic LKA of CTCs with early intervention before patients develop metastatic burden.

FUNDING INFORMATION

This work was supported by operating funds from BioCytics and Carolina BioOncology Institute.

CONFLICT OF INTEREST STATEMENT

JDP is owner and founder of both BioCytics and Carolina BioOncology Institute. RW and RBD receive salary from BioCytics; JM is a paid consultant for BioCytics. AA receives salary from Carolina BioOncology Institute.

Supporting information

Figure S1. CBOI‐BioCytics HAL is a novel delivery model with full stack, vertically integrated, cell manufacturing at the PoC. On the left is a list of the core capabilities enabling a vertically integrated PoC cell therapy center. On the right from top to bottom are photos of the clinical team, leukapheresis accreditation post‐inspection, and HAL team who work together in this multidisciplinary PoC ecosystem.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.