WO2018044888A1

WO2018044888A1 - Tumor vaccination systems, devices, and methods

Info

Publication number: WO2018044888A1
Application number: PCT/US2017/049118
Authority: WO
Inventors: James C. Chen; Llew Keltner; Alexei N. Naimushin
Original assignee: Chen James C; Llew Keltner; Naimushin Alexei N
Priority date: 2016-08-29
Filing date: 2017-08-29
Publication date: 2018-03-08

Abstract

Systems, devices, and methods are described for providing, among other things, improvements in treatment of abnormal tissues including cancer, utilizing light activated drug therapy. Improvements include methodologies and technologies for eliciting an antitumor immune response in a biological subject. Also described are one or more methodologies or technologies for treatment including light activated drug therapy and tumor vaccination. In an embodiment, a vaccine dose form includes an autologous tumor sample from at least one light activation drug therapy treated tumor; and an encapsulant.

Description

TUMOR VACCINATION SYSTEMS, DEVICES, AND METHODS

SUMMARY

This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary is not intended to identify key features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

In an aspect, the present disclosure is directed to, among other things, a vaccine dose form. In an embodiment, the vaccine dose form includes an autologous tumor sample from at least one light activation drug therapy treated tumor and an encapsulant. In an embodiment, the vaccine dose form includes an autologous tumor sample from at least one photosensitizer treated tumor and an encapsulant. In an embodiment, the vaccine dose form includes an autologous tumor sample from at least one tumor treated with a photothermal sensitizer or a photosensitizer, and an encapsulant. In an embodiment, the autologous tumor sample includes at least one of antigenic components, immunogenic cell components, and autologous tumor breakdown products. In an embodiment, the autologous tumor sample comprises one or more tumor antigen proteins. In an embodiment, the autologous tumor sample comprises tumor material from at least two separate intratumoral locations. In an embodiment, the autologous tumor sample comprises tumor material from at least three separate intratumoral locations. In an embodiment, the encapsulant is configured to allow the passage of at least one tumor antigen protein from within the encapsulant to an exterior environment, while substantially blocking passage of tumor cells received within the encapsulant.

In an aspect, the present disclosure is directed to, among other things, a vaccination device. In an embodiment, the vaccination device includes a photosensitizer assembly configured to deliver and activate a photosensitizer composition. In an embodiment, the vaccination device includes a vaccination assembly configured to implant one or more vaccine dose forms proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node. In an embodiment, the vaccination device includes a body structure including at least one anchoring component configured to anchor at least a portion of the vaccination device. In an embodiment, the vaccination device includes a tumor material harvesting assembly configured to retrieve an autologous tumor sample from a biological subject.

In an aspect, the present disclosure is directed to, among other things, a vaccination catheter. In an embodiment, the vaccination catheter includes a multi-lumen body structure including at least one lumen configured to receive and deploy a tumor harvesting assembly. In an embodiment, the vaccination catheter includes a multi-lumen body structure including at least one lumen configured to receive and deploy a photosensitizer assembly. In an embodiment, the vaccination catheter includes a multi- lumen body structure including at least one lumen configured to receive and deploy a vaccination assembly.

In an aspect, the present disclosure is directed to, among other things, a method including implanting a vaccine dose form including an autologous tumor sample proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node. In an embodiment, the method includes delivering a photosensitizer solution to a tumor prior to implanting the vaccine dose form.

In an aspect, the present disclosure is directed to, among other things, a method for eliciting an antitumor immune response in a biological subject. In an embodiment, the method for eliciting the antitumor immune response in the biological subject includes delivering a photosensitizer solution to a tumor within a biological subject and activating said photosensitized with a light capable of activating said photosensitizer. In an embodiment, the method for eliciting the antitumor immune response in the biological subject includes exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more tumor breakdown products.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURES 1A-1D are perspective views of a vaccine dose form according to one or more embodiments. FIGURE 2 is a perspective view of a vaccine dose form according to one embodiment.

FIGURE 3 is a perspective view of a vaccine dose form according to one embodiment.

FIGURE 4 shows a flow diagram of a method according to one embodiment.

FIGURE 5 shows a flow diagram of a method for eliciting an antitumor immune response in a biological subject according to one embodiment.

FIGURES 6-12 show a perspective view of a vaccination system according to one or more embodiments.

In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented here.

DETAILED DESCRIPTION

Described are one or more methodologies or technologies for eliciting an antitumor immune response in a biological subject. Also described are one or more methodologies or technologies for treatment including light activated drug therapy and tumor vaccination.

In an embodiment, treatment of major tumor masses using light activated drug therapy can significantly reduce overall patient immunosuppression by reducing the tumor's ability to generate and secrete immunosuppressive proteins, angiogenic factors, cytokines, small molecules, exosomes, and other immune modulating substances which promote tumor growth and spread. In an embodiment, such treatment approaches are crucial to enable an anti-tumor vaccine effect to reach maximal efficacy, and has been borne out in hundreds of cancer vaccine studies which consistently demonstrate the vaccines have minimal effects in patients with high tumor volumes and advanced cancers.

In an embodiment, harvesting a significant amount of treated tumor material at the time of the definitive therapy and at the point of care, and vaccinating the patient at disparate sites can markedly enhance the overall antitumor immune response in a very novel fashion. In an embodiment, one or more advantages of whole cell cancer vaccines are realized, including the activation of maximal numbers of anticancer immune cells recognizing multiple tumor antigens, without the well-known disadvantages, including the difficulty of obtaining whole tumor material. The preparation of whole tumor ly sates is time consuming, complex and difficult, requires special expertise and equipment which may not be available, expensive, and can lead to treatment delays. One or more of these disadvantages are avoided by the methodologies or technologies described herein. In addition, the ability to obtain tumor samples from different tumor regions at the time of the actual therapy is enabled, which greatly enhances convenience, efficacy, and maximizes the actual antitumor immunization effect. In an embodiment, treating the tumor mass first, prior to tumor sample harvesting, reduces the risk of bleeding when obtaining tumor samples, due to the well-known anti-vascular vessel closure effect of light activated photosensitizers. Treating the tumor mass also downstages the cancer or abnormal growth and reduces the well- known immune dysfunction associated with the tumor microenvironment. This immune corrective action enhances the antitumor activity of the subsequent vaccination process.

The preparation of tumor lysates is known to involve various methods of ex vivo tumor cell killing, which may include cell heating, freezing, irradiation with ionizing radiation, or using ultraviolet light. Ex vivo preparation requires specialized equipment, know how, and can be time consuming, difficult, and expensive. In contrast, the novel methodology enabled by the present disclosure enables creation of tumor lysate in a manner that is much easier, faster, less expensive, and significantly more convenient.

The vaccination procedure described in this disclosure requires minimal preparation, and is performed on site and at the time of the photoactivation, which is entirely novel, in terms of its efficiency, safety, efficacy, and convenience. The ability to vaccinate at more than one body site, and sequentially over a period of time if desired, is novel, and should increase the anti-tumor effect. Multiple vaccination sites also enable the use of more than one type of immune adjuvant or enhancer, in order to optimize the anti-tumor response. Patients may react more strongly to particular adjuvants and enhancers, and the use of multiple "test" sites allows for personalization of this phase of the therapy. A variety of dermal vaccination sites can be chosen such as the neck and supraclavicular region, the axillary region, and the groin/inguinal regions, which harbor numbers of accessible lymph nodes, which can react with the tumor antigens released from the vaccination capsules.

In an embodiment, a single use, disposable apparatus is enabled by this disclosure, which obviates all of the known problems related to re-sterilization and reuse of medical devices.

In an embodiment, a single percutaneous or bodily access point is enabled by the method and apparatus, which greatly reduces patient discomfort, risk of device dislodgement or migration, infection risk, bleeding, and other complications.

Different iterations of the described technologies and methodologies are enabled, for differing markets with differing requirements and financial restraints (i.e., first world, developing world). Human and animal patients can undergo this minimally invasive treatment at much lower cost, and with far fewer side effects, both short term and long term. The therapy is innocuous, and enables rapid, definitive treatment at the time of diagnosis, and can even be performed at the time of a biopsy, especially when the likelihood of cancer is very high. Benign lesions can also be treated in a very novel manner, and the immune system harnessed to aid in treatment in a manner not currently possible with existing therapies.

FIGURES 1A-1D show vaccine dose forms 102 in which one or more methodologies or technologies can be implemented such as, for example, eliciting an antitumor immune response in a biological subject. In an embodiment, the vaccine dose form 102 includes an autologous tumor sample 104 from at least one tumor and an encapsulant. In an embodiment, the autologous tumor sample 104 includes at least one of antigenic components, immunogenic cell components, and autologous tumor breakdown products. In an embodiment, the autologous tumor sample 104 comprises one or more tumor antigen proteins. In an embodiment, the vaccine dose form 102 is treated to ensure no viable tumor cells remain. For example, in an embodiment, the vaccine dose form 102 includes at least one of a photothermal sensitizer, a photosensitizer, and the like that is photoactivated prior to being placed proximate at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node. In an embodiment, the autologous tumor sample 104 is exposed to at least one of a photothermal sensitizer, a photosensitizer, and the like and phototreated prior to being incorporated into a vaccine dose form 102. In an embodiment, the autologous tumor sample 104 comprises tumor material from at least two separate intratumoral locations. In an embodiment, the autologous tumor sample 104 comprises tumor material from at least three separate intratumoral locations. In an embodiment, the autologous tumor sample 104 comprises tumor material from at least two tumors. In an embodiment, the autologous tumor sample 104 comprises tumor material from at least three tumors. In an embodiment, the autologous tumor sample 104 ranges from about 1 milligram to about 2 grams of tumor material.

In an embodiment, the vaccine dose form 102 includes an encapsulant 106. In an embodiment, the encapsulant 106 comprises at least one porous or permeable encapsulant material 108. In an embodiment, the encapsulant 106 is configured to allow antigenic and immunogenic cell components and breakdown products to elute from within the encapsulant 106 to an exterior environment, and to retaining whole cells. In an embodiment, the encapsulant 106 comprises at least one of collagens, polylactides, and hydrogels. In an embodiment, the encapsulant 106 comprises at least one optically transparent material. In an embodiment, the encapsulant 106 comprises at least one of hydrogel bead entrapment alginates, gelatin, carrageenan beads, gel beads, agar, agarose, polyacrylamide gels, and alginate gels. In an embodiment, the encapsulant 106 comprises one or more micro-meshes 110, micropores 112, or micro-perforations.

In an embodiment, the vaccine dose form 102 includes a semi-permeable encapsulant 114 comprising an autologous tumor sample. In an embodiment, the semipermeable encapsulant 106 is configured to permits the passage of tumor material of a first molecular weight or size, while substantially blocking passage of tumor material of a second molecular weight or size different from the first. In an embodiment, the semipermeable encapsulant 106 is configured to allow the passage of at least one tumor antigen protein from within the encapsulant 106 to an exterior environment, while substantially blocking passage of tumor cells received within the encapsulant 106.

In an embodiment, the vaccine dose form 102 includes a semi-permeable encapsulant having a micromesh sized and configured to allow the selective egress of immunogenic antigens, molecules, and tumor derived substances while substantially blocking preventing the egress of whole tumor cells received within the encapsulant 106.

In an embodiment, the vaccine dose form 102 includes at least one adjuvant. In an embodiment, the at least one adjuvant comprises at least one of alum salts, bacille Calmette-Guerin, bacterial products, chemokines, CpG oligonucleotides, cytokines, GM- CSF (granulocyte/macrophage colony stimulating factor), haptens, incomplete Freund's adjuvant, and interleukins.

In an embodiment, the vaccine dose form 102 includes at least one immune enhancer. In an embodiment, the at least one immune enhancer comprises at least one of a checkpoint inhibitor, a co-stimulatory molecule, an immune promoting cytokine, and immune-adjuvant. In an embodiment, the at least one immune enhancer comprises at least one of an anti-PD-l/PD-Ll inhibitor, mAbs nivolumab, MPDL-3280, and BMS-936559. In an embodiment, the at least one immune enhancer comprises at least one of an OX40 ligand, an immune costimulatory molecule from the B7 family, an immune costimulatory molecule from the CD28 family, an immune costimulatory molecule from the tumor necrosis factor (T F)/tumor necrosis factor receptor (TNFR) family, CD 137, and T cell activity enhancer.

In an embodiment, the vaccine dose form 102 includes at least one immunotherapy agents. In an embodiment, immunotherapy agents, immune enhancers, immunoadjuvants, adjuvants, and the like are injected into, or applied to the encapsulating unit after unit insertion. In an embodiment, different immune checkpoint inhibitors and co-stimulatory molecules increase the antitumor effect of vaccination. In an embodiment, immune enhancers, immunoadjuvants, adjuvants, and the like are injected locally or systemically. Non-limiting examples of immune checkpoint inhibitors include monoclonal antibodies (mAbs) including ipilimumab and tremelimumab. Non- limiting examples of immunotherapy agents include the anti-PD-l/PD-Ll inhibitor mAbs nivolumab, MPDL-3280, and BMS-936559. Non-limiting examples of co-stimulatory agents include OX40 ligand and other molecules belonging to two major families, the B7/CD28 family and tumor necrosis factor (TNF)/tumor necrosis factor receptor (TNFR) family. Further non-limiting examples of co-stimulatory agents include CD137 (also known as 4- IBB) costimulatory signal agents that enhances T cell activity.

Any number of immune adjuvants and enhancers can be trialed in each patient in order to maximize the antitumor immune response engendered by the vaccination process. These products can be injected systemically, though local injection or topical application at the vaccination site, or proximate to the vaccination site is preferred in order to reduce potential for systemic side effects. The local use of immune adjuvants and enhancers greatly reduces the systemic side effects due to the much lower concentration and volume of product used. Each vaccination site can be closely monitored and evaluated for a reactive response, and using this scheme, enables a personalized trial of different adjunct agents. The stronger the localized response from the adjuvant / enhancer, the greater will be the likelihood of a useful clinical response.

In an embodiment, cutaneous topical application of an immune boosting includes the use of either imiquimod or diphenylcyclopropenone, both of which are known to enhance the potential anticancer actions of dendritic cells.

In an embodiment, an immune adjuvant / enhancer is incorporated into the vaccine capsule, or injected in proximity to the capsule. Non-limiting examples adjuvants include Cytokines, Chemokines, Interleukins, Alum salts, Bacterial products such as Bacille Calmette-Guerin, Incomplete Freund's adjuvant, CpG oligonucleotides, Haptens, and the like.

In an embodiment, embolization can also be utilized to reduced arterial inflow from tumor feeding vessels reduces photosensitizer clearance. Embolic material increases light scattering for a front facing or slightly angled laser, which is rotatable to increase the total treated volume of tumor. The light source, which may be a laser or other coherent or incoherent light source can remain in the intravascular space or organ lumen.

In an embodiment, embolic material can be mixed into an optical clearing liquid solution such as mannitol, which increases light penetration. Light wavelengths that are normally associated with poor tissue penetration such as blue light can be used in conjunction with an optical clearing agent in order to enhance optical penetration depth in a very novel manner. Normally, blue light wavebands are associated with greatly increased photoactivation potential and light absorption by the photosensitizer. This is due to the large Soret band (characterized by large light absorption potential) typically found in this wavelength range for almost all clinically useful photosensitizers. Also, this embodiment enables the internal use of photosensitizers activated in a highly efficient manner using short waveband light for bulky lesions, rather than the typical use of short waveband light only for thin lesions and superficial lesions. Using this methodology and apparatus scheme enables very rapid and complete activation of photosensitizer, which greatly increases the speed at which the procedure can be accomplished. This reduces risk of infection, device dislodgement, patient discomfort, and increases convenience for the treating clinicians and the patient.

In an embodiment, the vaccine dose form 102 includes at least one of a photothermal sensitizer, a photosensitizer, and the like. Non-limiting examples of photothermal sensitizers include azo dyes, gold nanoparticles, graphene, metallo derivatives of porphyrins, porphyrinoid compounds, porphyrins, triphenylmethane derivatives, and the like. Non-limiting examples of photosensitizer include chlorophylls dyes, photosensitizers for PDT, porphyrins, and the like. Further non-limiting examples of photosensitizer include Allumera, aminolevulinic acid (ALA), Amphinex, Antrin, Azadipyrromethenes, BF-200 ALA, Cevira, Cysview, Foscan, Hexvix, Laserphyrin, Levulan, Lumacan, Metvix, mono-L-aspartyl chlorin e6 (NPe6), m- tetrahydroxyphenylchlorin (mTHPC), Photochlor, Photofrin, Photosens, Photrex, Silicon Phthalocyanine Pc 4, Visonac, Visudyne, and the like. Further non-limiting examples of photosensitizer include porphyrins, chlorins, bacteriochlorins, photosensitizing prodrugs such as aminolevulinic acid, phthalocyanines, other tetrapyrrole structures, hypericin, riboflavin, curcumin, xanthene dyes, methylene blue, various transition metal complexes, phenothiaziniums, some boron compounds, psoralens, anthraquinones, cyanine dyes, and the like.

In an embodiment, the vaccine dose form 102 includes an anchoring component 114 including at least one anchor for removably securing at least a portion of the vaccine dose form 102 proximate at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node. In an embodiment, the anchoring component 114 includes at least one of an adhesive, an anchor, a barb, a brace, a connector, an expandable component, a hook, a projection, a reversibly inflatable bladder, a screw, a staple, and a suture configured to removably secure the vaccine dose form 102 proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node. In an embodiment, the vaccine dose form 102 includes an anchoring component 114 having at least one mechanical or chemical means for attaching the vaccine dose form 102 to an in situ site proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node.

In an embodiment, vaccine dose forms 102 are preserved in a physiologic solution containing an antibiotic. In an embodiment, vaccine dose forms 102 kept frozen them, thus preserving the harvested treated tumor for later insertion at a later date. In an embodiment, in a vaccination scheme some of the treated tumor is inserted as a whole tumor vaccine at the time of photoactivation treatment, and weeks to months later, a secondary vaccination is performed. In an embodiment, the timing and scheduling of multiple vaccinations is optimized and guided by performance of clinical trials assessing the timing that produces the best antitumor responses.

In an embodiment, a vaccine dose form 102 is deposited in the dermal or subcutaneous region, adjacent to lymph nodes, lymphoid organs such as the spleen, or within a lymph node basin.

In an embodiment, the vaccine dose form 102 includes biocompatible and biodegradable encapsulant 106 materials. Non-limiting examples of biocompatible and biodegradable materials include collagens, polylactides, and the like. In an embodiment, the encapsulant 106 materials include optically transparent materials, which aids in assessing the treated tumor loaded into the individual capsules. In an embodiment, biodegradation rate can be adjusted to occur over hours to days, using a variety of biopolymers such as for example collagens, which minimize scarring, and can reduce tumor antigen leaching from the vaccination capsule.

In an embodiment, the vaccine dose form 102 comprises an encapsulating and cell immobilization capsule. In an embodiment, the vaccine dose form 102 incorporates immune enhancing substances, which can both attract tumor antigen recognizing immune cells, and/or enhance the numbers and antitumor activity of the immune cells. Non- limiting examples of immune effect stimulating and enhancing substances include checkpoint inhibitors, co-stimulatory molecules, immune promoting cytokines, immune- adjuvants, and the like. In an embodiment, relatively localized delivery of these immune promoting substances reduces the risk of systemic administration side effects, while simultaneously enabling a much greater immune stimulation effect utilizing a much lower concentration of immune promoter.

In an embodiment, the vaccine dose form 102 comprises biomaterials used for cell entrapment and immobilization. Non-limiting examples of biomaterials used for cell entrapment and immobilization include Gel beads, agar, agarose, Polyacrylamide gels, Alginate gels, Hydrogels, alginates, Gelatin, Carrageenan beads, and the like. Further examples of material for fabricating vaccine capsules, or implantable cell immobilization technology, can be found in Fundamentals of Animal Cell Encapsulation and Immobilzation Mattheus F.A. Goosen (1992); Cell Encapsulation Technology and Therapeutics Kuhtreiber, Willem et al (2013); The Encaptra drug delivery system developed by the biotech company Viacyte (San Diego, CA); each of which is incorporated herein by reference to the extent such subject matter is not inconsistent herewith.

In an embodiment, the disclosed technologies and methodologies comprise a point of care, single session treatment, including definitive tumor treatment and vaccination, which is highly efficient and convenient for the clinicians and the patients. In an embodiment, the effectiveness of the primary therapy and the secondary immunoadjuvant vaccination process can be monitored using immunotherapy assessment assays and measuring serum markers of inflammation such as C-reactive Protein and other acute phase proteins, interleukin 6 and other cytokines, transforming growth factor and other growth factors, and various chemokines.

FIGURE 2 shows a system 200 (e.g., a vaccination system, an antitumor immune response system, medical system, medical device system, a medical procedure monitoring system, or the like) in which one or more methodologies or technologies can be implemented such as, for example, for eliciting an antitumor immune response in a biological subject.

In an embodiment, the system 200 includes at least one vaccination device 202.

In an embodiment, the vaccination device 202 includes a photosensitizer assembly 204 configured to deliver and activate a photosensitizer composition. In an embodiment, the photosensitizer assembly 204 includes at least one reservoir having a photosensitizer composition. In an embodiment, the photosensitizer assembly 204 includes at least one reservoir and a microfluidic network, and is configured to dispense photosensitizer composition including one or more of chlorins, porphyrins, phthalocyanines, flavins, hypericins, psoralens, purpurins, cyanines, photosensitizer prodrugs, and methylene blue.

In an embodiment, the photosensitizer assembly 204 includes at least one reservoir and a microfluidic network, and is configured to dispense photosensitizer composition including from about 1 to 50 grams of mannitol, and from about 0.5 mg to about 5 grams of dimethyl sulfoxide (DMSO). In an embodiment, the photosensitizer assembly 204 includes at least one reservoir and a microfluidic network, and is configured to dispense photosensitizer composition including from about 2 milligrams (mg) to 50 grams of a photosensitizer.

In an embodiment, the photosensitizer assembly 204 includes at least one guidewire to facilitate placement of the photosensitizer assembly 204 proximate or within at least one tumor feeding vessel. In an embodiment, the photosensitizer assembly 204 includes at least one optical fiber operable to deliver an electromagnetic energy stimulus.

In an embodiment, the vaccination device 202 includes a vaccination assembly 206 configured to implant one or more vaccine dose forms 102 proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node. In an embodiment, the vaccination assembly 206 includes a dermal insertion needle. In an embodiment, the vaccination assembly 206 includes at least one guidewire.

In an embodiment, the vaccination device 202 includes a body structure including at least one anchoring component 208 configured to anchor at least a portion of the vaccination device 202. In an embodiment, the at least one anchoring component 208 includes at least one of an adhesive, an anchor, a barb, a brace, a connector, an expandable component, a hook, a projection, a reversibly inflatable bladder, a screw, a staple, and a suture.

In an embodiment, the vaccination device 202 includes a tumor material harvesting assembly 210 configured to retrieve an autologous tumor sample 104 from a biological subject. In an embodiment, the tumor material harvesting assembly 210 includes a flexible tumor harvesting needle. In an embodiment, the tumor material harvesting assembly 210 includes at least one needle sized and configured to retrieve an autologous tumor sample 104 from a tumor within a biological subject. In an embodiment, the vaccination device 202 includes a tumor material harvesting assembly 210 configured to retrieve tumor material from at least two separate intratumoral locations. In an embodiment, the vaccination device 202 includes a tumor material harvesting assembly 210 configured to retrieve tumor material from at least three separate intratumoral locations.

In an embodiment, benign and malignant tumors are sampled after one or more treatment sessions utilizing a tumor harvesting assembly. In an embodiment, the tumor harvesting assembly includes one or more of a core biopsy device, a fine needle aspiration device, and articulated core biopsy device, and the like. In an embodiment, a tumor harvesting assembly is incorporated into the treatment apparatus, or introduced after treatment prior to withdrawal of the entire treatment apparatus.

In an embodiment, a tumor material harvesting assembly 210 is introduced into the treated tumor substance over a previously placed guide wire, and utilized to withdraw a treated tumor tissue sample. In an embodiment, a tumor material harvesting assembly 210 includes one or more of a cutting type biopsy devices, suction and aspiration devices, automated and manual biopsy devices, and the like. In an embodiment, the tumor material harvesting assembly 210 includes one or more of morcellation devices using blades or bipolar energy, ultrasound vibration aspirators, variable speed rotating cutting devices, tumor fragmenting devices, and the like. In an embodiment, treated tumor material is cut, minced, or sonicated, and retrieved from at least one tumor location and region for later use as an inoculum for the vaccination process. In an embodiment, a vaccination catheter including a tumor harvester is placed and positioned optionally using image guidance, and tumor is retrieved from one or more regions that have been treated, thus increasing the probability of capturing a wide array of tumor related and specific antigens.

In an embodiment, harvested tumor material is isolated from normal tissue due to its containment in a catheter, and transferred directly to the encapsulation / cell immobilizing unit, thus preventing tumor cell seeding. In an embodiment, after tumor harvesting, the retrieved material is placed into capsules, films, or other encapsulating and cell immobilizing units for subsequent insertion into the cutaneous layer or deeper within the body. In an embodiment, surviving tumor cells are precluded from reestablishing a blood supply or metastasizing by the encapsulating unit, which only allows tumor antigen proteins and the like to escape.

In an embodiment, harvested tumor material is implanted in diverse lymph node basins which can be located in the dermis, or in proximity to deeper lymph node regions. In an embodiment, implanted harvested tumor material creates a multitude of tumor sensitized and activated sentinel nodes whose anticancer response can be augmented locally or systemically by for example adjuvants such as GM-CSF (granulocyte/macrophage colony stimulating factor).

In an embodiment, an immune response is stimulated by implanting a vaccine capsules proximate or within one or more implantation sites. Non-limiting examples of implantation sites include neck and supraclavicular regions, the axillary regions, the groin regions, the peritoneal cavities, the pleural spaces, any solid organ including the liver, the pancreas, the kidney, the brain, all body cavities, and the like. In an embodiment, vaccination capsules are anchored using, for example, a suture or a staple to prevent migration when used in a deeper body location. In an embodiment, a plurality of vaccination capsule is placed in proximity to another capsule if desired.

In an embodiment, vaccination capsules are inserted in proximity to tumors not specifically treated by photoactivation in order to achieve an immune attack. In the case of diffuse disease patterns such as a miliary pattern, peritoneal or pleural tumor spread, or malignancy invading bone, the capsules can be placed in the diseased region after treatment of a tumor elsewhere. In an embodiment, tumor invading critical structures are treated by way of partial treatment of the accessible, safer tumor portion using the photoactivation devices and methodology, followed by the vaccination procedure, which treats the otherwise untreatable remainder of the tumor which invades the critical structure.

In an embodiment, the tumor material harvesting assembly 210 including a Flexible Needle Harvesting Apparatus. An example of a flexible needle comprises of a wire wound pre curved or straight axis flexible needle with an OD (outer diameter) that allows ease of passage through the catheter lumen ID (inner diameter). An obturator or stylet, which is removable can aid passage of the flexible needle through the catheter. The treated tumor substance is then aspirated by a suction syringe device, which can be manual or automated.

In an embodiment, multiple tumor sites can be sampled around an axis or in a straight trajectory. In an embodiment, suction is used to enhance tumor capture and retention. In an embodiment, an obturator or stylet is optionally used to gently eject tumor specimen into the vaccination capsule device

In an embodiment, utilizing repeated needle tumor insertion and withdrawal with suction in different directions will load the needle to a greater degree, and enable ejection of a larger volume of tumor mass into more than one vaccination capsule. This technique minimizes the time and steps needed to harvest a significant amount of treated tumor material, and insures that no tumor comes into contact with normal tissues. In an embodiment, treated tumor samples can be primarily harvested from the tumor tissue proximate to the distal end of the device, which speeds up the entire process, and reduces the risk of harvesting untreated tumor regions. Tumor can also be harvested during the photoactivation process, which can reduce total procedural time. In an embodiment, rotational devices and / or ultrasonic vibration devices are utilized in accordance with this disclosure, in order to facilitate tumor harvesting after photoactivation. In an embodiment, the tumor material harvesting assembly 210 includes a coring device.

In an embodiment, after harvesting treated tumor with the aid of the catheter, a sample is withdrawn within a vaccination catheter, which reduces the risk of tumor seeding of normal tissue and blood. In an embodiment, the sample can be pushed into predesigned and constructed vaccine capsules, which are sterile and prepackaged. In an embodiment, the capsules are preferable elongate, narrow, cylindrical, and inserted using a needle. In an embodiment, the capsules are microporous in nature, allowing tumor antigens and debris to escape, while preventing the egress of whole tumor cells, which may be viable. In an embodiment, capsule material is preferably biodegradable, though a more permanent material can be used and later retrieved. In an embodiment, the elongate, narrow, cylindrical shape allows for maximal release of tumor antigen, while allowing for maximal exposure of immune cells to the vaccination site. Virtually any site in the body can be used as a vaccination destination, including the dermis, or deeper body locations, within lymph node basins, and including the interior of lymphoid organs including the spleen. In some patients, the vaccination capsule or capsules can be inserted prophylactically into organs that are likely to harbor, or to develop metastases. Examples include but are not limited to insertion of vaccination capsules into the brain of a patient with lung cancer, or insertion of the capsules into the spine of a patient with prostate cancer. In an embodiment, the elongate, narrow design of the vaccination capsule reduces the bleeding risk during and after insertion. The capsule is after-loaded with treated tumor and then sealed. The front of the capsule is pre-sealed and the rear of the capsule is open for tumor after-loading. The pre-sealed end optionally contains a protrusion with a thru- hole, which allows for a suture anchor, especially useful in cases where the vaccination capsule must be anchored to internal tissue in order to prevent migration and dislodgment. In an embodiment, simple crimping tool and crimping technique can be used to seal the capsule, preventing tumor cell escape. Alternatively, biocompatible glue can be used, such as cyanoacrylates used for tissue bonding and wound closures. In an embodiment, glue is applied to the open end of the vaccine capsule, sealing in the tumor sample. Alternatively, a biocompatible cap is applied over the open end.

In an embodiment, the tumor material harvesting assembly 210 includes one or more flexible or articulated needles. In an embodiment, a needle with a slightly larger diameter than the capsule, is used to insert the capsule into the vaccination site, similar to a birth control implant. The narrow shape of the vaccination cylinder reduces the risk of bleeding, and the use of a needle to insert the capsule minimizes the tissue stab wound used for placement, reducing infection risk and minimizing discomfort. Non-limiting examples of flexible needles include Spinflex needle by Veran Medical Technologies (St Louis, MO), Modified Colapinto needles, flexible needle as described by Ishikawa et al, Rosch Uchida needle by Cook Medical (Bloomington, IN), Flexible needle by Urotech GmbH (Achenmuhle, Germany), and the like. Further examples of needles can be found in U.S. Patent No. °8, 632,468, which is incorporated herein by reference to the extent such subject matter is not inconsistent herewith.

In an embodiment, the vaccination device 202 includes a tumor core retrieving device, which withdraws the treated tumor sample into a semipermeable capsule, which is localized or inserted into the dermal area of the skin surface. A number of core sampling devices have been described, including suction and cutting devices, rotating devices, aspiration devices, and grasping devices. Another embodiment can be a screw shaped device, such as the Rotex biopsy screw needle (marketed by Ursus Medical), which drills into and retrieves a tumor specimen. One or more tumor samples are retrieved by the device, which samples from at least one tumor site, and placed into the immunogenic capsule apparatus. In an embodiment, the screw device can optionally be biodegradable, and the screw emplaced into the capsule with associated treated tumor after withdrawal from the tumor. In one variation of this embodiment, the sterile capsule device contains an opening into which the tumor material is inserted, and then capped off in order to completely seal the device and prevent egress of tumor cells. Alternatively, the open end of the capsule can be crimped to ensure proper sealing. In an embodiment, the capsule can be composed of any biocompatible material, biodegradable or not. In an embodiment, the capsule incorporates a mesh design, or micro-perforations, which permits egress of immunogenic antigens, molecules, and other tumor derived substances, leading to the immunization effect, which may sensitize and activate antitumor immune cells of all types.

In another embodiment, treated tumor is aspirated manually using a syringe or an automated suction device into a catheter, which is withdrawn from the treatment site. The distal tip of the treated tumor containing catheter is positioned at the open end of the vaccination capsule, and the tumor material ejected into the vaccination capsule using a stylet or obturator which is inserted into the catheter. In an embodiment, at least one sterilized capsule or multiple capsules are arrayed and stabilized in a sterile tray, which allows for ease of treated tumor substance loading into each capsule. In an embodiment, tafter sealing the capsules by crimping the open end or placing a cap on the opening, a larger bore needle termed an insertion needle whose inner diameter is larger than the outer diameter of the capsule is used to first extract the capsule from the tray. The vaccination capsule can be extracted by the friction between the inner surface of the insertion needle and the outer surface of the vaccination capsule, or by slight pinching of the insertion needle as it surrounds the vaccination capsule. The sterile insertion needle is then used to insert the capsule into the dermal or deeper tissue site. The vaccination capsule can be ejected from the insertion needle into the dermis or deeper tissue site using a stylet or obturator. This process is repeated as desired, till all capsules are delivered to the body sites for lymph node activation. Preferably, a separate insertion needle is used with each vaccination capsule to reduce infection risk, rather than resterilizing and reusing one insertion needle repeatedly.

In an embodiment, in order to enable retrieval of multiple tumor cores from different tumor locations after treatment, a distensible tine apparatus contained within a sheath can be deployed, with more than one tine extended into the treated tumor mass simultaneously. A number of hollow coring needles can be secondarily deployed over the extended tines, enabling multiple tumor cores to be harvested, followed by withdrawal into the sheath. This maneuver prevents tumor track seeding, and allows for treated tumor to be placed into multiple capsules for implantation at disparate body sites.

In an embodiment, implantation of treated tumor tissue remote or distant to the originally treated tumor mass has the advantage of exposing more tumor breakdown products and antigens to potentially less immunosuppressed lymph node regions. The antitumor immune response can thus be greatly enhanced over what can be achieved by simply treating the target tumor mass in situ, since the tumor mass creates a hostile microenvironment which suppresses and abrogates effective antitumor responses.

In an embodiment, since the light and drug treatment can cause closure of tumor blood vessels, the risk of bleeding from tumor sampling is greatly reduced. In an embodiment, the harvesting assembly 210 allows for repeated sampling from the treated tumor mass, including sampling from different tumor regions if desired. Due to the known propensity for tumors to harbor heterogeneous cell lines, this aspect of the device overcomes a key problem of a "one size fits all" approach inherent in many cancer vaccines. In one embodiment, the tissue sample is stored in a physiologic solution, which permits the light and drug photosensitizing tissue breakdown process to continue. Alternatively, the harvested tumor mass is encapsulated and immobilized immediately after tumor specimen harvest, or stored for hours to days after the original treatment. The treated tumor tissue is then returned to the treated patient in the form of a vaccine. The vaccination site is any convenient skin surface, lymph node basin, tumor node draining site, lymphoid organ, or other conventional and nonconventional locations.

In an embodiment, intracorporeal placement of the treated tumor distant to the main tumor mass enables antitumor immune response to be more robust since the harvested tumor antigen mass is available to immune system cells which are less suppressed and more functional, being distant to the immunosuppressive tumor microenvironment.

In an embodiment, the whole tumor inoculum is inserted or placed proximate to any immune cell containing anatomical structures including intradermal or subcutaneous skin sites, intramuscular sites, adjacent to cervical nodes, axillary nodes, inguinal nodes, or injected into or adjacent to other lymphoid organs such as the thymus, spleen, and the bone marrow.

FIGURE 3 shows a vaccination catheter 302 in which one or more methodologies or technologies can be implemented such as, for example, for eliciting an antitumor immune response in a biological subject. In an embodiment, the vaccination device 302 includes a multi-lumen body structure 304 comprising at least one lumen 306 configured to receive and deploy a tumor harvesting assembly 210. In an embodiment, the vaccination device 302 includes a multi-lumen body structure 304 comprising at least one lumen 308 configured to receive and deploy a photosensitizer assembly 204. In an embodiment, the vaccination device 302 includes a multi-lumen body structure comprising at least one lumen configured to receive and deploy a vaccination assembly 206. In an embodiment, the vaccination assembly 206 is configured to implanting from 1 to about 10 vaccine dose forms 102 proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node.

FIGURE 4 shows method 400. At 410, the method 400 includes implanting a vaccine dose form 102 including an autologous tumor sample 104 proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node. At 412, implanting the vaccine dose form 102 including the autologous tumor sample 104 includes implanting from 1 to about 10 vaccine dose forms 102 proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node. At 414, implanting the vaccine dose form 102 including the autologous tumor sample 104 includes implanting a plurality of the vaccine dose forms 102 in at least one dermal region and at least one deeper body region. At 416, implanting the vaccine dose form 102 including the autologous tumor sample 104 includes implanting a plurality of the vaccine dose forma 102 in 1 week to 1 month intervals. At 418, implanting the vaccine dose form 102 including the autologous tumor sample 104 includes implanting the vaccine dose form 102 including implanting harvested tumor material in diverse lymph node basins.

In an embodiment, the method 400 includes pre-treating autologous tumor sample 104 to ensure no viable tumor cells remain. For example, in an embodiment, the method 400 includes incorporating at least one of a photothermal sensitizer, a photosensitizer, and the like within the tumor sample 104 and photo-activating it prior to being incorporated into a vaccine dose form 102.

In an embodiment, the method 400 includes incorporating at least one of a photothermal sensitizer, a photosensitizer, and the like with a vaccine dose form 102 that is photoactivated prior to being placed proximate at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node. In an embodiment, the method 400 includes treating and exposing the autologous tumor sample 104 to at least one of a photothermal sensitizer, a photosensitizer, and the like that is photoactivating prior to being incorporated into a vaccine dose form 102.

At 420, the method 400 includes delivering a photosensitizer solution to a tumor prior to implanting the vaccine dose form 102. At 422, delivering a photosensitizer solution to the tumor includes delivering a photosensitizer composition including one or more of chlorins, porphyrins, phthalocyanines, flavins, hypericins, psoralens, purpurins, cyanines, photosensitizer prodrugs, and methylene blue. At 424, delivering a photosensitizer solution to the tumor includes delivering photosensitizer composition including from about 1 to 50 grams of mannitol, and from about 0.5 mg to about 5 grams of dimethyl sulfoxide (DMSO).

FIGURE 5 shows method 500 for eliciting an antitumor immune response in a biological subject.

At 510, the method 500 for eliciting an antitumor immune response in a biological subject includes delivering a photosensitizer solution to a tumor within a biological subject.

At 512, delivering the photosensitizer solution to the tumor within a biological subject includes delivering a photosensitizer composition including one or more of chlorins, porphyrins, phthalocyanines, flavins, hypericins, psoralens, purpurins, cyanines, photosensitizer prodrugs, and methylene blue. At 514, delivering the photosensitizer solution to the tumor within a biological subject includes delivering a photosensitizer composition including from about 1 to 50 grams of mannitol, and from about 0.5 mg to about 5 grams of dimethyl sulfoxide (DMSO).

At 520, the method 500 for eliciting an antitumor immune response in a biological subject includes exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more tumor breakdown products. At 522, exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more tumor breakdown products includes exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to autologous tumor sample 104 comprises tumor material from at least two separate intratumoral locations. At 524, exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more tumor breakdown products includes exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to autologous tumor sample 104 comprises tumor material from at least three separate intratumoral locations.

At 530, the method 500 for eliciting an antitumor immune response in a biological subject includes exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more antigens.

At 540, the method 500 for eliciting an antitumor immune response in a biological subject includes exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more checkpoint inhibitors.

At 550, the method 500 for eliciting an antitumor immune response in a biological subject includes exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more co-stimulatory molecules.

At 560, the method 500 for eliciting an antitumor immune response in a biological subject includes exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more immune promoting cytokines.

At 570, the method 500 for eliciting an antitumor immune response in a biological subject includes exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more immune adjuvants.

In an embodiment, the method 500 for eliciting an antitumor immune response in a biological subject includes one or more tumor breakdown products to ensure no viable tumor cells remain. For example, in an embodiment, the method 500 for eliciting an antitumor immune response in a biological subject includes pretreating one or more tumor breakdown products with at least one photothermal sensitizers prior to exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to the one or more tumor breakdown products. In an embodiment, the method 500 for eliciting an antitumor immune response in a biological subject includes pretreating one or more tumor breakdown products with at least one photosensitizer prior to exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to the one or more tumor breakdown products. In an embodiment, the method 500 for eliciting an antitumor immune response in a biological subject includes photoactivation at least one photothermal sensitizers within the one or more tumor breakdown products prior to exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to the one or more tumor breakdown products. In an embodiment, the method 500 for eliciting an antitumor immune response in a biological subject includes photoactivation at least one photosensitizer within the one or more tumor breakdown products prior to exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to the one or more tumor breakdown products.

Prophetic Example A

After identification of a tumor to be treated, the lesion is accessed either percutaneously, by way of a naturally occurring or artificially created orifice, or via an intravascular route. Standard image guidance, or intracorporeal navigation techniques are utilized to emplace a steerable guidewire proximate to, or within the tumor substance. A catheter, which may incorporate a miniature ultrasound imaging transducer, is passed over the guidewire, and the photosensitizer drug solution is injected into the tumor substance. Either intratumoral drug injection, or intravascular drug delivery through a tumor- feeding vessel distributes the drug within the tumor substance, by way of the catheter. Utilizing external or internal ultrasound, the photosensitizer distribution and approximate concentration is imaged, and additional photosensitizer injected as needed. Image guidance of this phase of treatment reduces the risk of drug distribution outside of the lesion to be treated. Using this form of guidance and control, the concentration of photosensitizing drug is normal tissue prevented or minimized. The light device, which is preferentially but not exclusively comprised of a laser and optical fiber assembly, is introduced internally, by way of the catheter. The optical fiber tip is inserted intratumorally, or at the tumor edge and light is delivered to the tumor substance, which activates the photosensitizing drug. Correct placement and orientation of the light device is enabled using image guidance.

After photoactivation, the light device is withdrawn, and the tumor harvesting assembly introduced. At least one tumor sample is harvested, and preferably multiple samples from different tumor regions are collected. The harvested treated tumor material is immobilized and encapsulated, and inserted at selected body sites. The sites can be proximate to lymph nodes and/or other lymphoid organs, and range from intradermal to deep internal sites. Imaging, lab tests, clinical assessment, and patient reported outcomes are used to assess results and guide further therapy. Data from all treatment phases including pre and post treatment are captured in various formats for analysis. The use of treated tumor substance to induce an anticancer immune response creates a potentially highly efficacious and safe therapeutic vaccine which is entirely novel in terms of ease and speed of creation and use.

Another embodiment and methodology consists of more than one guide wire and catheter, each of which is inserted into the single access point during the same treatment episode. The use of multiple guidewires and catheters enables tumor masses in different bodily locations to be treated by way of one access site. The guidewires are directed toward different tumors by way of differing paths which may be intravascular, and / or traversing different tissues and organs, or different organ lumens. Therefore, the disclosure enables a single or multiple guidewires to access one or more tumors that are proximate or distant.

Prophetic Example B

A standard steerable guidewire is inserted via a vascular conduit such as the radial artery or femoral artery. Alternatively, a percutaneous route can be used, as in performance of a biopsy. The guidewire can also be positioned by way of a natural orifice, or an artificially created orifice such as a fistula or a stoma. In an embodiment, image guidance, intracorporeal navigation, or freehand technique is utilized to ensure that the guidewire is properly positioned. A catheter with at least one lumen, but with preferably more than one lumen is positioned over the guidewire. The catheter can be inserted over the guidewire, or using a monorail catheter configuration, or using other catheter / guidewire designs. Once properly positioned, the catheter can be used to enable photoactive drug injection. Drug injection can occur by direct drug delivery through a catheter lumen, or using a needle guided into the tumor mass by the catheter. A flexible needle may be used for drug injection. The optical fiber coupled to a light source, which may be a laser, or noncoherent light source is the positioned in order to activate the drug. After completion of the photoactivation process, treated tumor is harvested using the catheter. The channel previously used for the drug delivery procedure or any other lumen can be used for the tumor harvesting process. A cutting device, a grasping device, a screw device, a sonication device, or any other type of harvesting device is used to obtain tumor samples for use as a vaccine. The catheter lumen containing the tumor sample can be withdrawn using the harvesting device or aspirated through the channel.

If desired and deemed necessary, the drug injection, and/or the photoactivation process can be directed at different tumor regions, especially in a larger tumor mass. This feature is enabled by directing the steerable guidewire in different directions, followed by repositioning the catheter into different orientations. This maneuver also permits tumor harvesting from different tumor regions, which aids in the diversity of tumor antigens available for the vaccination process, with the goal of increasing the overall antitumor immune response.

Also novel to this disclosure is the opportunity to direct the guide wire to adjacent tumor masses, enabling multiple disparate tumor sites to be treated at the same sitting. The feature enables even more tumor mass to be downstaged, which reduces overall immunosuppression and patient symptoms, and provides for even more treated tumor material for vaccination purposes.

Another embodiment consists of a flexible, steerable guidewire embedded in a multi-lumen catheter. The catheter also contains an embedded optical fiber connected to a light source, which may be internal or external to the body. In an embodiment, the catheter further contains a lumen for drug injection and delivery of any desired fluids, photosensitizers, embolic material, optical clearing agents, immune enhancing solutions, or the like. For example, injection of a photosensitizer along with embolic material can slow the clearance of the photosensitizer from the tumor mass, thus prolonging the high concentration of photoactive drug, which in turns speeds up the light activation process according the law of reciprocity. Also, an optical clearing agent such as mannitol can be injected along with the photosensitizer, which can enhance the photoactivation process by reducing the concentration of blood cells, which absorb the applied light. This method also enhances the effectiveness of shorter waveband light sources which overlap the large absorption wavebands of the photosensitizer, which in turn increases the speed, depth, and completeness of photoactivation in a novel manner. The previously mentioned lumen or channel may also optionally be used to pass the tumor tissue biopsy device, used for sampling of treated tumor tissue, which in turn acts as the vaccine substrate. Prophetic Example C

A patient is discovered to harbor a breast mass, which is highly likely to be a cancerous lesion. A needle, which may be flexible or rigid, is inserted into the lesion using standard image guidance, which may consist of ultrasound imaging. The catheter, which allows for photosensitizer injection, optical fiber positioning, and treated tumor harvesting is fed over the needle, which in this case is essentially acting also as a guidewire. The treatment of the lesion is performed immediately after biopsy of the lesion to establish the nature of, and degree of malignancy, if any. If the lesion is benign, then no further treatment is required. If the lesion is malignant, then the vaccination process can be implemented, with placement of vaccination capsules in the axillary regions bilaterally as an example. Enlarged and accessible lymph nodes harboring cancer can also be treated in a similar fashion in order to reduce potential for tumor spread and to convert the malignant node, which may contribute to a dismal prognosis into an anticancer site instead. In this example, rather than waiting for treatment which may be spread out over many weeks or even months, the patient receives definitive treatment in a highly novel, efficient and convenient manner, which is unprecedented. Patient anxiety is greatly reduced, and the side effects and cost of treatment are minimal compared to standard therapies, which include surgery, radiation, chemotherapy and other drug therapies. Well known long- term side effects of standard therapy, which include physical, cognitive, and mental conditions, are avoided by the technologies and methodologies described herein.

Prophetic Example D

A patient, in this example is a companion animal with cancer, is treated using photoactivation and vaccination. Surgery is avoided, and many otherwise ineligible companion animals can undergo a definitive therapy, rather than premature euthanasia. Prophetic Example E

A patient with a benign lesion, in this case a large neurofibroma in an inoperable state is treated using photoactivation and vaccination. Since even benign tumors harbor potentially immunogenic antigens, the vaccination process can be utilized in a very novel fashion. Activation of the immune system against neurofibroma antigens may also provide therapeutic effects against smaller lesions, which may number in the hundreds, and for which there is no effective and safe therapy. The large lesion is greatly reduced in size, and normal tissue sparing is maximized. Tumors that are invading critical structures such as nerves or blood vessels, the brain and spinal cord, can be treated using the described technologies and methodologies in a much more effective and safe manner compared to existing therapies. Prophetic Example F

The general patient status/ treatment / immune status ecosystem can be positively influenced to optimize outcomes by incorporating other types of treatments, interventions, and lifestyle changes which can have a significant impact on quality of life, tolerability of main treatments, survivorship issues and challenges, and ultimate outcomes. In an embodiment, a variety of mobile device or laptop/PC based applications, which are aimed at assessing and optimizing:

Sleep hygiene

Diet / supplements / nutritional status

Exercise program

Stress reduction

Access to support groups for patient and family, financial aid and assistance, social and other routine services

Mental and emotional well - being

The combined impact on quality of life and other patient outcomes is captured and analyzed in order to optimize the overall therapeutic plan, which includes direct tumor treatment, antitumor immunization, and the helpful adjuncts and lifestyle modifications listed above.

Many conventional anticancer therapies are associated with significant short term and long term cognitive problems and issues. It is anticipated that the present disclosure will not be associated with undesirable cognitive issues, and therefore this aspect of treatment (along with other well-known current cancer treatment side effects) can be tested and analyzed for effect, and compared with standard therapies.

Prophetic Example G

In an embodiment, development of a registry, which facilitates post market surveillance, and facilitates additional device and methodology innovations and approvals. Safety data is continuously captured, along with technical implementation data and outcome data. Quality measures are assessed on an ongoing basis, which aids in reimbursement. Data can be incorporated into electronic medical records of individual patients, allowing for grouping and analysis of device function and use, patient descriptors and characteristics, and short and long term outcomes, which include quality of life assessments. As empirical data accumulates, algorithms are generated and refined on an ongoing basis, which guide therapeutic decisions, and provide predictive models, which inform patients and clinicians. The use of and discovery of new surrogate endpoints is facilitated, which can greatly reduce development costs and speed the application process and approvals. Complications and medicolegal risks are reduced due to the enhanced information flow and availability, as well as enhanced documentation, which in turn lowers the overall therapy cost. Software based and hardware based simulations can be developed, enabling rehearsal, based on real world data in order to improve user proficiency and reduce treatment times, which will also contribute to cost reduction.

In an embodiment, generation and use of written templates that can be filled out by healthcare providers or others involved with other treatment aspects. The templates, which may be standardized and/or customized, can reduce the time spent capturing and analyzing patient, treatment, and provider data. The templates can be incorporated into mobile devices as an option, and data entered manually or verbally. Various formats are utilized, depending on the purpose. For example, patient, treatment, and outcome data supporting a clinical trial is very different than that entered for a basic science study of the immune effects relating to the vaccination capsule. Data captured on site can be stored by a centralized repository, which may be cloud based. In an embodiment, methodologies and technologies include capture and analysis of radiologic images, videos of the procedure, and other visual data, which can be entered into the global database. The training of healthcare providers is also facilitated by this aspect of the disclosure. Prophetic Example H

The following drug/light dosages and types, and modes of administration, and other specifications serve as examples further clarifying and enabling the successful implementation of the disclosure, but are not intended to limit the scope of the disclosure in any way.

Light wavelengths and wavebands ranges from the ultraviolet to the infrared, substantially overlapping at least one absorption band of the photosensitizing drug.

Light is delivered in a pulsed fashion, intermittently, or continuously at a total energy ranging from 10 Joules to 50,000 Joules per lesion per treatment episode, over a time period range of 5 minutes to 5 hours. Non-limiting examples of examples of photosensitizer include chlorins, porphyrins, phthalocyanines, flavins, hypericins, psoralens, purpurins, cyanines, photosensitizer prodrugs, and the like. In an embodiment, the photosensitizer includes Methylene blue.

The amount of photosensitizer drug delivered to each lesion ranges from 2 milligrams (mg) to 50 grams, and is best determined and optimized empirically, and will be dependent on tumor volume and location.

The photosensitizing solution optionally incorporates 1 to 50 grams of mannitol as an optically clearing agent, and 0.5 mg to 5 grams of DM SO as a tissue penetrant aid, delivered in a physiologic solution such as normal saline.

The treated tumor sample that comprises part of the vaccine ranges from 1 mg to 2 grams per vaccination capsule. Between 1 and 10 vaccination capsules can be inserted into any lymph node basin, or proximate to tumor at any particular time point. The vaccination capsules can be inserted at the time of tumor photoactivation treatment, or at 1 week to 1 month intervals. The number of vaccination sites or regions can range from 1 to 10, and can be dermal or in deeper body regions.

In an embodiment, vaccination capsules are created from various biopolymers and biocompatible substances with rapid dissolution and absorption properties. One example is the use of common gelatin capsules, which are biocompatible and readily breakdown, enabling release of tumor antigens soon after insertion into the body.

The adjuvant or adjuvants that serve to enhance the antitumor immune effect include but are not limited to topical agents and injectable agents. An example of a topical agent is imiquimod, which is applied to the skin as a cream, in an area ranging from 1 centimeter squared to 1 meter squared. The location can encompass the vaccination site, or be remote. GM-CSF is an example of an injectable agent, injected in the vicinity of the vaccination capsule or capsules at a dose ranging from 10 micrograms to 2 grams per site.

FIGURE 6 shows a percutaneous and intravascular access to tumor. In an embodiment, though access can also be accomplished through other tissue layers or by way of natural or surgical orifices. A flexible, steerable guidewire, a flexible needle, and a flexible catheter provide a route to the tumor mass. In an embodiment, the catheter has at least one lumen, which provides a guide for an optical fiber, drug injection, embolization, tumor harvesting, and other desired actions. In an embodiment, the optical fiber is coupled to a laser or other light source, and can be aimed at different tumor regions in the case of treatment of large lesions. It should also be noted that multiple disparate lesions can be treated by advancing the guidewire to different organ locations or bodily regions using the single body surface access point.

Referring to FIGURE 7, a vaccination catheter 302 is configured to includes one or more of a channel or lumen 702 for a fiber optic assembly a photosensitizer assembly, or the like; a channel or lumen 704 for a guidewire assembly; a channel or lumen 706 for a vaccination assembly; a channel or lumen 708 for a tumor harvesting assembly, and the like

Referring to FIGURE 8, in an embodiment, treated tumor is readily harvested using a flexible needle or using other biopsy capable devices previously described. The amount of tumor harvested is virtually unlimited, and after harvest is ejected into sterile, biocompatible and biodegradable cylindrical capsules which are implanted within the dermal layer or deeper in the body, in proximity to lymph nodes. The capsule is preferably sealed at the distal end during manufacture, and then is sealed at the proximal end using a crimping tool after tumor is loaded into the capsule interior. This precludes viable tumor cell escape. The capsule is perforated, allowing for tumor antigen to leach into the surrounding tissue in proximity to lymph nodes. Any single or combination of vaccine adjuvants can be readily incorporated to the capsule, or injected or applied to the surrounding tissues near the capsule, in order to enhance the antitumor vaccination effect. Non-limiting examples of systemic use of adjuvants and immune effect enhancers included cyclophosphamide, which has been shown to reduce immunosuppressive T regulatory cells.

Referring to FIGURE 9, the block diagram outlines the data capture scheme according to one embodiment. As data accumulates, the following nonexclusive list of questions can be answered with increasing accuracy:

Optimal volume of tumor to be treated

Optimal timing and scheduling of treatment (intensity of treatment)

Optical vaccination sites and vaccination schedule

Optimal volume of treated tumor per vaccine capsule

Optimal methods of accessing and illumination tumor Optimal photosensitizer, drug delivery method, optimal dosing

Optimal adjuvant selection, use, and combination therapies

Maximization of overall antitumor immune response

Best response biomarkers and imaging

Capture of overall use data can be related to profit / cost / loss data enabling various types of economic analyses. Measurement of quality parameters is also enabled, by capturing pertinent data. Decision making applications can be developed using treatment parameters and outcomes data, which facilitates clinician ease of use.

Ultimately, a massive database is generated which supports treatment refinements and algorithms, continued research and development, publications and presentations, reimbursement, and label expansion. The database is protected by encryption methods and techniques suitable and appropriate for the healthcare environment.

Referring to FIGURE 10, in an embodiment, treated tumor extraction device is comprised of a hollow flexible needle, which is pre-curved, and extended through the main access catheter after tumor treatment. The flexible needle is rotated and extended manually or using an automated extension device, optionally under image guidance. A suction apparatus, which may be a manually controlled syringe, or a motorized device, serves to aspirate treated tumor into the needle. When the needle and suction device has extracted the desired volume of material the flexible needle is withdrawn from the main access catheter and transferred externally from the body to allow for tumor sample loading into vaccine capsules. The entire process is performed utilizing sterile technique. The vaccine capsules are optionally arrayed in a holding device, which steadies the capsules for ease of loading. A stylet or obturator is used to gently eject the tumor samples into the vaccine capsules. The cylindrical capsules are sealed by crimping the open end and optionally capped at the crimped end. The vaccine capsules are then loaded into a larger diameter needle for insertion into the vaccination site.

Referring to FIGURE 11, in an embodiment, the treatment of tumors that are invading critical structures, thus rendering very difficult and risky to treat using conventional therapies. The tumor is partially treated, sparing the critical structure, followed by treatment of the remaining lesion using an immune attack induced by the vaccination capsule or capsules. Down staging of the lesion using the described technologies and methodologies can lead to other follow on treatments such as surgery becoming feasible as well.

Referring to FIGURE 12, in an embodiment, an index lesion, which is the main and most dangerous cancer deposit in the prostate is treated using photoactivation. The guidewire / needle is directed using a transrectal route, using transrectal ultrasound, or by way of a transperineal route, or transurethral route. Smaller, satellite cancer lesions are treated using the vaccination process, thus sparing normal tissues.

A liver cancer lesion is treated by photosensitizer injection followed by photoactivation using the tumor using the intravascular route. Treated tumor is harvested, and placed into a vaccination capsule. The capsule is inserted in the vicinity of the treated tumor to augment the antitumor immune response. The flexible and steerable guidewire / needle is then directed through the treated tumor using image guidance such as ultrasound, to an adjacent tumor which is then similarly treated. This methodology and technique is efficient, and enables a single access site to be utilized repeatedly. This technique spares the patient multiple punctures and multiple passes of the hardware used for photoactivation and vaccination capsule immunization.

While various aspects and embodiments have been disclosed herein, other aspects and embodiments are contemplated. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

Claims

CLAIMS The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A vaccine dose form, comprising:

an autologous tumor sample from at least one light activation drug therapy treated tumor; and

an encapsulant.

2. The vaccine dose form of claim 1, wherein the autologous tumor sample includes at least one of antigenic components, immunogenic cell components, and autologous tumor breakdown products.

3. The vaccine dose form of claim 1, wherein the autologous tumor sample comprises one or more tumor antigen proteins.

4. The vaccine dose form of claim 1, wherein the autologous tumor sample comprises tumor material from at least two separate intratumoral locations.

5. The vaccine dose form of claim 1, wherein the autologous tumor sample comprises tumor material from at least three separate intratumoral locations.

6. The vaccine dose form of claim 1, wherein the autologous tumor sample comprises tumor material from at least two tumors.

7. The vaccine dose form of claim 1, wherein the autologous tumor sample comprises tumor material from at least three tumors.

8. The vaccine dose form of claim 1, wherein the autologous tumor sample ranges from about 1 milligram to about 2 grams of tumor material.

9. The vaccine dose form of claim 1, wherein the encapsulant comprises at least one porous or permeable encapsulant material.

10. The vaccine dose form of claim 9, wherein the encapsulant is configured to allow antigenic and immunogenic cell components and breakdown products to elute from within the encapsulant to an exterior environment, and to retaining whole cells.

11. The vaccine dose form of claim 1, wherein the encapsulant comprises at least one of collagens, polylactides, and hydrogels.

12. The vaccine dose form of claim 1, wherein the encapsulant comprises at least one optically transparent material.

13. The vaccine dose form of claim 1, wherein the encapsulant comprises at least one of hydrogel bead entrapment alginates, gelatin, carrageenan beads, gel beads, agar, agarose, polyacrylamide gels, and alginate gels.

14. The vaccine dose form of claim 1, wherein the encapsulant comprises one or more micro-meshes, micropores, or micro-perforations.

15. The vaccine dose form of claim 1, wherein the encapsulant comprises a semi-permeable encapsulant.

16. The vaccine dose form of claim 15, wherein the semi-permeable encapsulant is configured to permit the passage of tumor material of a first molecular weight or size, while substantially blocking passage of tumor material of a second molecular weight or size different from the first.

17. The vaccine dose form of claim 15, wherein the semi-permeable encapsulant is configured to allow the passage of at least one tumor antigen protein from within the encapsulant to an exterior environment, while substantially blocking passage of tumor cells received within the encapsulant.

18. The vaccine dose form of claim 15, wherein the semi-permeable encapsulant is incudes a micromesh sized and configured to allow the selective egress of immunogenic antigens, molecules, and tumor derived substances while substantially blocking preventing the egress of whole tumor cells received within the encapsulant.

19. The vaccine dose form of claim 1, further comprising:

at least one adjuvant.

20. The vaccine dose form of claim 19, wherein the at least one adjuvant comprises at least one of alum salts, bacille Calmette-Guerin, bacterial products, chemokines, CpG oligonucleotides, cytokines, GM-CSF (granulocyte/macrophage colony stimulating factor), haptens, incomplete Freund's adjuvant, and interleukins.

21. The vaccine dose form of claim 1, further comprising:

at least one immune enhancer.

22. The vaccine dose form of claim 21, wherein the at least one immune enhancer comprises at least one of a checkpoint inhibitor, a co-stimulatory molecule, an immune promoting cytokine, and immune-adjuvant.

23. The vaccine dose form of claim 21, wherein the at least one immune enhancer comprises at least one of an anti-PD-l/PD-Ll inhibitor, mAbs nivolumab, MPDL-3280, and BMS-936559.

24. The vaccine dose form of claim 21, wherein the at least one immune enhancer comprises at least one of an OX40 ligand, an immune costimulatory molecule from the B7 family, an immune costimulatory molecule from the CD28 family, an immune costimulatory molecule from the tumor necrosis factor (T F)/tumor necrosis factor receptor (T FR) family, CD 137, and T cell activity enhancer.

25. The vaccine dose form of claim 1, further comprising:

at least one photothermal sensitizer or photosensitizer.

26. The vaccine dose form of claim 1, further comprising:

an anchoring component including at least one anchor for removably securing at least a portion of the vaccine dose form proximate at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node.

27. The vaccine dose form of claim 26, wherein the anchoring component includes at least one of an adhesive, an anchor, a barb, a brace, a connector, an expandable component, a hook, a projection, a reversibly inflatable bladder, a screw, a staple, and a suture configured to removably secure the vaccine dose form proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node.

28. The vaccine dose form of claim 1, further comprising:

an anchoring component having at least one mechanical or chemical means for attaching the vaccine dose form to an in situ site proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node.

29. A vaccination device, comprising:

a photosensitizer assembly configured to deliver and activate a photosensitizer composition; and

a vaccination assembly configured to implant one or more vaccine dose forms proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node.

30. The vaccination device of claim 29, further comprising:

a body structure including at least one anchoring component configured to anchor at least a portion of the vaccination device.

31. The vaccination device of claim 30 wherein the at least one anchoring component includes at least one of an adhesive, an anchor, a barb, a brace, a connector, an expandable component, a hook, a projection, a reversibly inflatable bladder, a screw, a staple, and a suture.

32. The vaccination device of claim 29, wherein the photosensitizer assembly includes at least one reservoir having a photosensitizer composition.

33. The vaccination device of claim 29 wherein the photosensitizer assembly includes at least one reservoir and a microfluidic network, and is configured to dispense photosensitizer composition including one or more of chlorins, porphyrins, phthalocyanines, flavins, hypericins, psoralens, purpurins, cyanines, photosensitizer prodrugs, and methylene blue.

34. The vaccination device of claim 29 wherein the photosensitizer assembly includes at least one reservoir and a microfluidic network, and is configured to dispense photosensitizer composition including from about 1 to 50 grams of mannitol, and from about 0.5 mg to about 5 grams of dimethyl sulfoxide (DMSO).

35. The vaccination device of claim 29 wherein the photosensitizer assembly includes at least one reservoir and a microfluidic network, and is configured to dispense photosensitizer composition including from about 2 milligrams (mg) to 50 grams of a photosensitizer.

36. The vaccination device of claim 29 wherein the photosensitizer assembly includes at least one guidewire and at least one tumor feeding vessel.

37. The vaccination device of claim 29 wherein the photosensitizer assembly includes at least one optical fiber operable to deliver an electromagnetic energy stimulus.

38. The vaccination device of claim 29, wherein the vaccination assembly includes a dermal insertion needle.

39. The vaccination device of claim 29, wherein the vaccination assembly includes at least one guidewire.

40. The vaccination device of claim 29, further comprising:

a tumor material harvesting assembly configured to retrieve an autologous tumor sample from a biological subject.

41. The vaccination device of claim 40, wherein the tumor material harvesting assembly includes a flexible tumor harvesting needle.

42. The vaccination device of claim 40, wherein the tumor material harvesting assembly includes at least one needle sized and configured to retrieve an autologous tumor sample from a tumor within a biological subject.

43. The vaccination device of claim 29, further comprising:

a tumor material harvesting assembly configured to retrieve tumor material from at least two separate intratumoral locations.

44. The vaccination device of claim 29, further comprising:

a tumor material harvesting assembly configured to retrieve tumor material from at least three separate intratumoral locations.

45. A vaccination catheter, comprising:

a multi-lumen body structure including

at least one lumen configured to receive and deploy a tumor harvesting assembly,

at least one lumen configured to receive and deploy a photosensitizer assembly, and

at least one lumen configured to receive and deploy a vaccination assembly.

46. A method, comprising:

implanting a vaccine dose form including an autologous light activation drug therapy treated tumor sample proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node.

47. The method of claim of claim 46, wherein implanting the vaccine dose form including the autologous tumor sample includes implanting from 1 to about 10 vaccine dose forms proximate or within at least one of a lymph node, a lymphoid organ, a lymph node basin, and a lymph node.

48. The method of claim of claim 46, wherein implanting the vaccine dose form including the autologous tumor sample includes implanting a plurality of the vaccine dose forms in at least one dermal region and at least one deeper body region.

49. The method of claim of claim 46, wherein implanting the vaccine dose form including the autologous tumor sample includes implanting a plurality of the vaccine dose forms in 1 week to 1 month intervals.

50. The method of claim of claim 46, wherein implanting the vaccine dose form including implanting harvested tumor material in diverse lymph node basins.

51. The method of claim of claim 46, further comprising:

delivering a photosensitizer solution to a tumor prior to implanting the vaccine dose form.

52. The method of claim 51, wherein delivering a photosensitizer solution to the tumor includes delivering a photosensitizer composition including one or more of chlorins, porphyrins, phthalocyanines, flavins, hypericins, psoralens, purpurins, cyanines, photosensitizer prodrugs, and methylene blue.

53. The method of claim 51, wherein delivering a photosensitizer solution to the tumor includes delivering photosensitizer composition including from about 1 to 50 grams of mannitol, and from about 0.5 mg to about 5 grams of dimethyl sulfoxide (DMSO).

54. A method for eliciting an antitumor immune response in a biological subject, comprising:

delivering a photosensitizer solution to a tumor within a biological subject; and exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more tumor breakdown products.

55. The method for eliciting an antitumor immune response in a biological subject of claim 54, wherein delivering the photosensitizer solution to the tumor within a biological subject includes delivering a photosensitizer composition including one or more of chlorins, porphyrins, phthalocyanines, flavins, hypericins, psoralens, purpurins, cyanines, photosensitizer prodrugs, and methylene blue.

56. The method for eliciting an antitumor immune response in a biological subject of claim 54, wherein delivering the photosensitizer solution to the tumor within a biological subject includes delivering a photosensitizer composition including from about 1 to 50 grams of mannitol, and from about 0.5 mg to about 5 grams of dimethyl sulfoxide (DMSO).

57. The method for eliciting an antitumor immune response in a biological subject of claim 54, wherein exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more tumor breakdown products includes exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to autologous tumor sample comprises tumor material from at least two separate intratumoral locations.

58. The method for eliciting an antitumor immune response in a biological subject of claim 54, wherein exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more tumor breakdown products includes exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to autologous tumor sample comprises tumor material from at least three separate intratumoral locations.

59. The method for eliciting an antitumor immune response in a biological subject of claim 54, further comprising:

exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more antigens.

60. The method for eliciting an antitumor immune response in a biological subject of claim 54, further comprising:

exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more checkpoint inhibitors.

61. The method for eliciting an antitumor immune response in a biological subject of claim 54, further comprising:

exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more co-stimulatory molecules.

62. The method for eliciting an antitumor immune response in a biological subject of claim 54, further comprising:

exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more immune promoting cytokines.

63. The method for eliciting an antitumor immune response in a biological subject of claim 54, further comprising: exposing at least one of a lymph node, a lymphoid organ, and a lymph node basin to one or more immune adjuvants. In an embodiment, the autologous tumor sample 104 is exposed to at least one of a photothermal sensitizer, a photosensitizer, and the like and phototreated prior to being incorporated into a vaccine dose form 102.

64. The method for eliciting an antitumor immune response in a biological subject of claim 54, further comprising:

pretreating one or more tumor breakdown products with at least one photothermal sensitizers prior to exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to the one or more tumor breakdown products.

65. The method for eliciting an antitumor immune response in a biological subject of claim 54, further comprising:

pretreating one or more tumor breakdown products with at least one photosensitizer prior to exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to the one or more tumor breakdown products.

66. The method for eliciting an antitumor immune response in a biological subject of claim 54, further comprising:

photoactivation at least one photothermal sensitizers within the one or more tumor breakdown products prior to exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to the one or more tumor breakdown products.

67. The method for eliciting an antitumor immune response in a biological subject of claim 54, further comprising:

photoactivation at least one photosensitizer within the one or more tumor breakdown products prior to exposing the at least one of a lymph node, a lymphoid organ, and a lymph node basin to the one or more tumor breakdown products.