WO1999053030A1

WO1999053030A1 - Method and system for managing immunocompetent cell batches for delayed use

Info

Publication number: WO1999053030A1
Application number: PCT/FR1999/000810
Authority: WO
Inventors: André Lefesvre; Patrick Rambaud
Original assignee: Lefesvre Andre
Priority date: 1998-04-08
Filing date: 1999-04-08
Publication date: 1999-10-21

Abstract

The invention concerns a method for managing immunocompetent cell batches belonging to human subject from whom said sets have been removed for future use on said subjects or relatives. Each immunocompetent cell batch associated with a subject is packaged and stored in a cryogenic site among a plurality of cryogenic sites, then transferred on request to a cell treatment centre. Said method provides individual preservation of immunocompetent elements and the possibility, if it is so desired, of culturing them with growth thereof. It aims at protecting the immunity and genetic capital from being altered during the individual's lifetime. The invention is particularly useful for reinforcing immune activity and gene therapy.

Description

"METHOD AND SYSTEM FOR MANAGING LOTS OF IMMUNO-COMPETENT CELLS FOR DELAYED USE"

The present invention relates to a method for managing batches of immunocompetent cells, in particular lymphocytes or monocytes, for deferred use. It also relates to a management system for implementing the method according to the invention.

Scientific and clinical studies have highlighted the therapeutic properties of the self-use of lymphocyte and monocytic derivatives which in particular contributes to an increase in cellular immunity.

One promising application of this therapeutic method concerns the possibility of strengthening the immunity of a patient at a time in his life when this strengthening proves necessary or vital or to maintain this immunity throughout his life.

However, an important difficulty to be overcome lies in the availability of a patient's lymphocytes or monocytes over periods of time which could be between several months and several decades. Cryogenic storage techniques are already known which are now widely used in many fields of human and animal biology. In particular, banks have been set up for the conservation and storage of biological elements.

WO89 / 04168 discloses a method of isolating and preserving hematopoietic cells from fetal and neonatal blood. This process is aimed in particular at the therapeutic use of fetal and neonatal cells for hematopoietic reconstitutions or in gene therapy, and can be implemented for the cryopreservation of fetal or neonatal blood cells for the purpose of autologous reconstitution. - 2 -

Uno-competent im cells (lymphocytes, phagocytic cells: monocytes, macrophages) play a central role in the immune system. In particular, lymphocytes store information during life and are the support of the memory of cellular and humoral immunity.

This library, lymphocyte in particular, but also the entire immune system, is enriched during life, as the individual encounters foreign organisms, during viral, parasitic or bacterial infections. It is thanks to it that the body can minimize the impact of infections during life. The mechanism of action of cellular immunity is known. Information is stored in particular in the walls of lymphocytes, as shown by the transfer factor and numerous publications. This mechanism also contributes to defense against malignant cells.

On the one hand, this memory is partially erased over time, as shown by the need to practice vaccination reminders to maintain effective protection. Regarding humoral immunity, antibody levels drop, quickly for IgM, more slowly for IgG and IgA. On the other hand, errors are introduced over time and immunity often becomes less effective over the years. It is because of this deterioration that infections like ^" the flu are much more serious in the elderly. It would therefore be beneficial to be able to keep the information acquired throughout life.

Samples can be taken at any age, as soon as the immune system is mature, either by peripheral blood test, or by leukopheresis, or by - 3 -

marrow removal. These samples retain more important information, since they are complete and living cells, than that transmitted by the transfer factor which is only an extract from the lymphocyte wall. The significant value of the transfer factor is widely proven.

However, it turns out that the current infrastructure and methods in terms of storage and management of biological batches are not adapted to the specific application of long-term deferred self-injection which requires very long-term management of batches of immunocompetent cells.

The aim of the invention is to propose a method for managing batches of immunocompetent cells, which makes it possible to conserve the information acquired throughout life, with a total guarantee of storage and availability in the very long term.

This objective is achieved by storing cells of the immune system at different periods of life so that they can be called upon later if necessary, in particular:

- occurrence of an uncontrolled acute infection,

- persistence of a chronic infection,

- appearance of a malignant disease, - appearance of a disease affecting the immune system itself,

- prevention of these diseases in a breast recipient.

According to the invention, the method for managing batches of immunocompetent cells comprises, for a given human subject:

- packaging and storage of batches of immunocompetent cells in one or more storage centers, a constitution and an enrichment of a personal library of immunocompetent cells from the successively sampled batches, this personal library preserving a sum of immune information stored in the immunocompetent cells sampled, and,

- in response to a request for treatment for the benefit of said human subject:

- a processing of all or part of the immune information accumulated in said personal library, and

- a location of one or more stored batches of immunocompetent cells, followed by a transfer of this or these batches to a requesting cell processing center.

The management method according to the invention may also include a plan for sampling batches of immunocompetent cells at different stages in the life of each human subject benefiting from this method. This sampling plan can include sampling steps at predetermined ages from the human subject, as well as unscheduled sampling steps conditioned by particular events in the life of the human subject. Thus, with the method according to the invention, it becomes possible to preserve the immune and genetic capital from any alteration during the life of an individual by carrying out an individual conservation of immuno-competent elements with the ability to make them. , if desired, a growing crop.

It is indeed possible to defrost an aliquot of the immuno-competent or immune cells stored, to culture them, to stimulate their functions for example with interleukin 2 or interleukin 12, - 5 -

then to reinject them into the patient, either by venous, or lymphatic, or local route. The therapeutic effect can be rapid. This process is not invasive. It does not introduce foreign cells into the body, since they are autologous cells. There is therefore no fear of rejection phenomenon, the HLA systems being compatible.

The conservation of these cells also allows a delayed genetic analysis which, by comparison, can reveal mutations which have occurred in the meantime. Preserving the plasma can also allow the identification of unknown infections at the time of collection.

In a preferred embodiment of the method according to the invention, each batch of lymphocytes associated with a subject is packaged and stored in a cryogenic storage site among a plurality of cryogenic storage sites, then transferred on demand from this site storage to a cell processing center to be reused, and each collection phase is associated with the collection, on the one hand, of personal data relating to the subject collected and on the other hand, of data relating to the collection.

Thus, such a method provides patients with the guarantee of a conservation of their lymphocytes over the long term, with the prospect of being able to have them at any time to among other things strengthen their immune system. It then becomes possible to give people back their previous immunity and to transmit cellular immunity, under rational and reliable management conditions, and in addition to have access to their genetic code corresponding to the date of blood collection. - 6 -

Preferably, at the end of a sampling phase, the lymphocytes collected are packaged in the form of a plurality of batches of lymphocytes. This allows flexible and efficient management of reinjections, without fear of having to thaw a batch of lymphocytes in excessive quantity compared to specific needs.

An advantageous implementation of the method according to the invention consists in that the batches of immunocompetent cells are stored in several geographically distinct cryogenic storage sites. This characteristic aims to increase the safety of storage of the lymphocytes or monocytes collected. More generally, in the management method according to the invention, the concept of deferred use covers both the field of self-use in the form in particular of self-injection, of use of transfer factor obtained from lymphocyte samples, or use of monocytes, or use of culture of lymphocytes with growth factors such as interleukin 2, and the field of uses of parentage, in particular in gene therapy, in particular the reading of the genetic code and the use of lymphocytes or monocytes taken from parents. The batches of lymphocytes or monocytes can for example be reused after cell culture in the presence of cell mediators, such as interleukin 2, for therapeutic purposes.

According to another aspect of the invention, a system is proposed for managing samples of immunocompetent cells, implementing the method according to the invention, this system being located in: a plurality of sampling and packaging centers for batches of immunocompetent cells, - a plurality of cryogenic storage sites intended to receive batches of immunocompetent cells,

- a plurality of cell processing centers for batches of immunocompetent cells, and - one or a plurality of batch management centers for immunocompetent cells, linked by means of communications to the sampling centers, to the cryogenic storage sites and to cell processing centers, characterized in that it comprises: means for constituting and enriching, from said batches successively sampled, a personal library of immuno-competent cells, this personal library retaining a sum of stored immune information in the immuno-competent cells taken,

means for processing all or part of the immune information accumulated in said personal library, in response to a request for treatment for the benefit of said human subject,

means for locating one or more stored batches of immunocompetent cells, and

- means to transfer this or these batches to a requesting cell processing center. In an advantageous embodiment, the management system further comprises means for establishing, for each human subject benefiting from said system, a plan for sampling batches of immuno-competent cells during their lifetime, and means for transmitting to one or more of the sampling and packaging centers for instructions and information relating to the execution of the sampling plan. Preferably, the management center or centers cooperate with a rapid logistics center to route the batches of immunocompetent cells from the cryogenic storage sites to the cell processing centers.

Furthermore, the management system according to the invention further comprises means for collecting personal data relating to patients subjected to lymphocyte or monocyte samples from the plurality of sampling centers.

Other features and advantages of the invention will appear in the description below. In the appended drawings given by way of nonlimiting examples:

- Figure 1 is a block diagram of the method and system for managing lymphocyte samples according to the invention; FIG. 2 illustrates the respective flows of direct debits, personal data and management data, resulting from the implementation of the management method according to the invention; and

- Figure 3 illustrates the relationships between reinjection, storage and management sites, within a management system according to the invention.

We will now describe an example of implementation of the method for managing lymphocyte or monocytic samples, at the same time as the corresponding management system, with reference to FIG. 1.

A first phase I concerns the collection and production of lymphocyte or monocytic batches. The following steps are carried out during a phase I carried out in a specialized CT center: data collection, in particular data relating to tissue grouping, and information relating to a patient i, - 9 -

- a blood sample from this patient,

- treatment of the blood drawn and separation of the lymphocytes and / or monocytes,

- cell identification, - fractionation to produce a set of lots of lymphocytes and / or monocytes,

- a preparation of lymphocytes and / or monocytes, including inter alia, possibly dehydration,

- Freezing and cryogenic storage of n batches of lymphocytes and / or monocytes Li, ι, Lj _. , _j , L _ifn , in a suitable refrigeration system, for example in a gas refrigeration atmosphere.

It should be noted that the separation and fractionation operations can be integrated and carried out within a cytopheresis apparatus. Furthermore, the cell identification step, which can implement various known identification techniques, can take place at other stages of phase I depending on technical specifications. The batches of frozen lymphocytes and / or monocytes are then distributed in different sites or storage banks S _A , S _κ , S _L. Storage of batches of lymphocytes is secure and managed. This management implements a database supplied with data collected during each sampling and storage phase I. The batches of immunocompetent cells could thus be stored over very variable durations ranging from a few days to several tens of 'years subject to the guarantee of good conservation of lymphocytes or monocytes over the long term. Furthermore, the principle of not storing all of a patient's batches in the same site contributes greatly to security of supply. - 10 -

When a therapeutic indication concerning a patient who has benefited from this management process recommends the use of lymphocytes or monocytes, phase II of the process is then undertaken. The company managing the process is contacted and receives a request for a batch of immunocompetent cells stored and managed on behalf of this patient. By interrogating the database, a batch belonging to this patient is determined and located in one of the storage sites S _A , S _κ , S _L of the set of sites ES. After localization and cell identification, the batch concerned is forwarded by rapid transport to a CR cell processing center which may also be the center from which the initial sample was taken.

The reuse phase (for example, reinjection) comprises for example: reception of the batch including an identification check which may in particular include a reading of a bar code and tissue grouping,

- defrosting of the batch,

- a new cell identification, resuspension of the lymphocytes or monocytes in a culture medium, - quality control and safety operations, and

- reuse of lymphocytes in the patient.

During this re-use phase II, new data relating to the patient may again be collected for the purposes of statistical studies and processing.

We will now describe the management process in terms of flow, with an analysis of the transfers of biological elements, personal data and - 11 -

data relating to direct debits and storage, with reference to FIG. 2. From any patient using the services of a direct debit management company at any time Tl, the following transfers are made:

- a transfer of biological elements constituted by LY lymphocytes or monocytes removed and separated,

- a transfer of personal data DP collected during direct debits, subject to compliance with the legal provisions specific to each state,

- a transfer of data and parameters directly associated with direct debits and essential for the management of direct debit stocks.

Each of these types of transfer leads to collection processes: a collection of batches of immunocompetent cells with centralized management and diversified storage sites, a collection of personal data to feed statistical databases, and a collection of data from samples to constitute a database for managing batches of immunocompetent cells.

When a phase II of reuse, for example in the form of a reinjection, is decided at a time Tl + ΔT, the following transfers are made: a transfer of a batch of immunocompetent cells from a storage site to a cell processing center, - transfer of the data and parameters associated with this batch, and

- a transfer of updated personal data on this patient, which is collected during the reuse phase. - 12 -

We will now describe the conditions for carrying out a reuse phase in the context of the management method according to the invention, more particularly in terms of geographic location and logistics, with reference to FIG. 3.

On a given territory, which can be a continent, a state, a region, or an urban community, centers of cytopheresis or CR _X , CR _K lymphocyte therapy are set up. These centers, intended to receive patients Pi, Pj, Px, Py who have joined a sample-reuse program implementing the management method according to the invention, are in communication by TL link means such as networks of closed or open communication (Internet) to one or more MC centers for managing lymphocyte or monocyte storage, which can be located anywhere in the world. This MC management center is in permanent communication by appropriate communication means SL

(dedicated links or open network such as the Internet) with all of the storage sites S _A , .., S _L. Furthermore, the management center MC cooperates with a rapid logistics center AL which controls a set of rapid dispatch platforms AP _A , AP _L near which the storage sites are preferably located. As an example of implementation of the management method according to the invention, a patient j contacts (1), on medical indication, a center for cytopheresis or CRi reuse of his choice, for example the center closest to home. him. The CRi cell processing center consults on a terminal connected to the MC management center and transmits (2) a batch request to it. The management center MC queries the management database and locates a batch of Lj immunocompetent cells corresponding to this patient in one of the - 13 -

storage sites. In the event of diversified multiple storage, the storage site closest to the CR _X cell processing center is chosen. The management center MC transmits (3) the request to the selected storage site S _A and contacts (4) the fast logistics center AL. The storage site S _A then extracts the batch concerned and immediately transmits it to the rapid dispatch platform AP _A which has been previously activated (5) by the rapid logistics center AL. Lot Lj is then routed (β) by the rapid means available, preferably by plane, to the CRi cell processing center.

It should be noted that each patient adhering to such a program generally has a stock of batches of immunocompetent cells which makes it possible for example to spread over time successive self-uses, for example in the form of self- injections, for the purpose of strengthening the immune system or gene therapy or other, or even to use massively, if necessary, the stock of lymphocytes or monocytes thus constituted.

The management method according to the invention is preferably materialized in the form of software installed on information management and processing systems which can be located in batch management centers and be linked to a set of sites. local IT in cytopheresis, fast logistics and storage centers.

Of course, the invention is not limited to the examples which have just been described and numerous modifications can be made to these examples without departing from the scope of the invention. Thus, it is possible to provide, within the framework of the sampling and reuse phases, additional technical steps according to imperatives - 14 -

medical and security constraints. The means of communication implemented between the various operational and management centers can be of any kind. Furthermore, the information collected within the framework of the management method according to the invention can advantageously be processed for statistical purposes, with applications in the field of prevention and insurance.

Claims

- 15 - CLAIMS

1. A method for managing batches of immunocompetent cells belonging to human subjects from which these batches were taken for deferred use, characterized in that it comprises, for a given human subject:

- packaging and storage of batches of immunocompetent cells successively sampled, in one or more storage centers, building up and enriching a personal library of immuno-competent cells from the batches sampled, this personal library accumulating a sum of immune information stored in the immuno-competent cells collected, and,

- in response to a request for treatment for the benefit of said human subject:

2. Method according to claim 1, characterized in that it further comprises a plan for sampling batches of immunocompetent cells at different stages in the life of a human subject benefiting from said method.

3. Method according to claim 2, characterized in that the sampling plan comprises stages of sampling at predetermined ages of the human subject. - 16 -

4. Method according to claim 3, characterized in that the sampling plan further comprises unscheduled sampling steps conditioned by particular events in the life of the human subject.

5. Method according to any one of the preceding claims, characterized in that each batch of immuno-competent cells associated with a subject is packaged and stored in a cryogenic storage site among a plurality of cryogenic storage sites. then transferred on demand from this storage site to a cell processing center to be reused on this subject or a relative of this subject, and in that each collection phase is associated with a collection, on the one hand, of personal data relating to the subject sampled and secondly, data relating to the sample.

6. Method according to claim 5, characterized in that at the end of a sampling phase, the immuno-competent cells sampled are fractionated and packaged in the form of a plurality of batches of immuno-competent cells.

7. Method according to claim 6, characterized in that for the same subject, the batches of immunocompetent cells are stored in several geographically distinct cryogenic storage sites.

8. Method according to claim 7, characterized in that it comprises, in response to a request sent by a cellular processing center for a given patient, a localization of a batch of immuno-competent cells - 17 -

belonging to this patient and a transfer of this batch to the requesting cell processing center.

9. Method according to any one of the preceding claims, characterized in that batches of immuno-competent cells are reused in the form of self-injections.

10. Method according to any one of the preceding claims, characterized in that batches of immuno-competent cells are reused to produce transfer factors.

11. Method according to any one of the preceding claims, characterized in that batches of immuno-competent cells are reused on a parent of the sample, for the purpose of gene therapy.

12. Method according to any one of the preceding claims, characterized in that the batches of immunocompetent cells are reused after cell culture in the presence of cell mediators, such as interleukin 2, for example, for therapeutic purposes.

13. Method according to any one of the preceding claims, characterized in that the batches of immuno-competent cells are reused to carry out a deferred genetic analysis.

14. Method according to any one of the preceding claims, characterized in that the batches of immunocompetent cells are reused to recover the - 18 -

trace of unknown infections at the time of collection of said lots.

15. System for managing samples of immunocompetent cells, implementing the method according to any one of the preceding claims, this system being located in: a plurality of centers for sampling and packaging batches of immunocompetent cells, - a plurality of cryogenic storage sites intended to receive batches of immunocompetent cells,

a plurality of cell processing centers for batches of immunocompetent cells, and

one or a plurality of centers for managing batches of immunocompetent cells, linked by means of communications to the sampling centers, to the cryogenic storage sites and to the cell processing centers, characterized in that it comprises: means for constituting and enriching, from successively sampled batches, a personal library of immuno-competent cells, this personal library retaining a sum of immune information stored in the immuno-competent cells sampled,

- means for processing all or part of the immune information accumulated in said personal library, in response to a request for treatment for the benefit of said human subject, - means for locating one or more stored batches of immuno-competent cells, and

- means to transfer this or these batches to a requesting cell processing center. - 19 -

16. The system as claimed in claim 15, characterized in that it further comprises means for establishing, for each human subject benefiting from said system, a plan for sampling batches of immuno-competent cells during its life, and means to transmit to one or more of the direct debits direct instructions in relation to this direct plan.

17. System according to one of claims 15 or 16, characterized in that the management center cooperates with a rapid logistics center to route the batches of immuno-competent cells from the cryogenic storage sites to the cell processing centers.

18. System according to one of claims 15 to 17, characterized in that it further comprises means for collecting personal data relating to patients subjected to lymphocyte or monocyte samples from the plurality of sampling centers.

19. System according to any one of claims 15 to 18, characterized in that each storage site is connected to a rapid shipping platform.