Overview of HITV Therapy
HITV therapy (Human Initiated Therapeutic Vaccine) is an immunotherapy specialized for advanced cancers such as stage IV and recurrent cancer. This therapy maximizes the capabilities of Dendritic Cells, the command center of the immune system, and achieves much higher response rate compared to conventional methods by locally acting immunotherapy, which is normally classified as a systemic therapy*1. This therapy has almost no side effects and has led to the cure of many patients.
Dendritic Cells
Dendritic Cells are immune cells named in 1973 by the late Professor Ralph Marvin Steinman (1943-2011) of Rockefeller University in the United States. In the 1990s, it was discovered that Dendritic Cells play a central role in the immune system, recognizing foreign substances that enter the body and transmitting that information to T cells, which are responsible for immune attack.
Professor Steiman's award of the Nobel Prize in Physiology or Medicine in 2011 also served as a catalyst for the spread of cancer treatment using Dendritic Cells.
History of HITV Therapy
HITV Therapy began in 1996 when its inventor, Dr. Kenichiro Hasumi (Chairman of the Hasumi International Research Foundation), used Dendritic Cells to bring malignant lymphoma into remission. Subsequently, to further advance research on Dendritic Cells, Dr. Hasumi began collaborative research with University of Maryland in the United States. This basic research is continuing to date. HITV therapy has made rapid progress since a case in 2005 when a case of head and neck cancer was cured by injecting Dendritic Cells directly into the tumor was reported. After that, Dr. Hasumi established a treatment method called "combination of radiation therapy and intratumoral administration of Dendritic Cells" and "combination of chemotherapy and intraarterial administration of Dendritic Cells," which have proven effective in treating many cancer patients. In 2011, Dr. Hasumi began intratumoral administration of CTL (killer T cells), further improving the therapeutic effect of HITV therapy.
Since 2021, Dr. Hasumi has introduced a treatment method of Dendritic Cell administration alone without radiation therapy or chemotherapy, which has been steadily achieving results.
*1 Systemic therapy: Treatment performed on the whole body, such as anticancer drugs and hormone therapy. Local therapy refers to treatments such as surgery or radiation that limit the treatment area. HITV therapy greatly improves the therapeutic effect by locally acting on immunotherapy, which is originally a systemic therapy. The feature of HITV therapy is that Dendritic Cells are directly administered into tumors. By having Dendritic Cells learn practical cancer information, they induce immune cells that attack cancer cells effectively. This will be explained in the next page.
Mechanisms Leading to Cure of Cancer
What distinguishes HITV Therapy from other Dendritic Cell therapies is the "intratumoral administration" of Dendritic Cells (DCs), which our doctors administer DCs directly into the tumor. The mechanism is explained below.
HITV therapy efficiently teaches immune cells "live" cancer information.
Dendritic Cells are the key to the immune system, responsible for transmitting information about cancer cells as enemy to immune cells in charge of attacking. In other words, if Dendritic Cells can transmit more detailed information about the target cancer cells to those immune cells, the accuracy of cancer attack will be further improved. Therefore making Dendritic Cells learn the latest cancer information is important for the success of immunotherapy. HITV therapy teaches immune cells "live cancer information" by directly administering Dendritic Cells into the tumor. This method makes it possible to efficiently induce CTLs (killer T cells), the immune cells in charge of attacking cancer cells that act most specifically on cancer cells.
This intratumoral administration procedure has been performed more than 10,000 times, and is now capable of treating tumors anywhere in the body (except for brain tumors). While other institutions may have used intratumor delivery of Dendritic Cells, most have been limited to superficial tumors or sites close to the skin. Intratumor delivery without site-specific administration is rare, even worldwide.
Shrinking and Eradicating Tumors
HITV therapy is expected to have the following four effects, which work synergistically to reduce or eliminate cancer tumors.
Suppression of Tumor Inflammation
The biggest challenge in cancer immunotherapy is the inflammation that occurs during treatment. When dendritic cells are administered alone into a tumor, a strong immune response is generated, but the tumor becomes more susceptible to inflammation, so special care is required. If inflammation occurs in the tumor, the symptoms may accelerate rapidly and the tumor may become irreversible. It is known that inflammatory cytokines*2 are involved in tumor inflammation. HITV therapy can suppress the onset of inflammation by administering inflammatory cytokine antibody drugs together with Dendritic Cells.
*2 Inflammatory cytokines: Cytokines that cause various inflammatory symptoms in the body. Cytokines are proteins mainly secreted by immune system cells.
Tumor Vaccination
CTLs (killer T cells) are the main immune cells that attack cancer cells. By administering Dendritic Cells into the tumor, these Dendritic Cells can learn live cancer information and vaccinate the tumor. After that, the Dendritic Cells mature in the tumor or lymph nodes, and CTLs (killer T cells) are induced in about two weeks.
Blood Purification
In the case of recurrent cancer or advanced cancer with stage IV multiple organ metastasis, cancer cells overflow into the blood. Even if the tumor is treated with surgery or radiation therapy, if these cancer cells in the blood are not removed, recurrent metastasis will occur.
Chemotherapy and immunotherapy are effective in removing cancer cells from the blood. However, chemotherapy damages not only cancer cells but also normal cells, so side effects are a major problem. In HITV therapy, CTLs (killer T cells) that act specifically on cancer cells are produced by "vaccinating tumors" and are released into the blood. These CTLs travel through the body in the bloodstream, finding and eliminating cancer cells. The blood purification effect of HITV therapy is the key to preventing recurrence and metastasis.
High Antitumor EffectHITV-induced CTL Therapy
The CTLs (killer T cells) induced in peripheral blood by HITV therapy recognize highly antigenic cancer information, so a strong antitumor effect can be expected. In cases of multiple organ metastasis, or if new lesions or areas where the treatment is incomplete are discovered after treatment, these CTLs (killer T cells) can be collected from the blood, cultured, and massproduced, and then administered directly to the lesion, leading to tumor shrinkage. CTL therapy can be described as a versatile treatment that not only provides "systemic control" by producing CTLs in the body and purifying the blood, but also provides "local control" by administering them intratumorally.
Treatment Steps
HITV therapy consist of the following seven steps. The initial treatment plan is very important. The patient should discuss the treatment plan thoroughly with the physician and agree on the treatment method, duration, and cost before proceeding with HITV therapy.
Initial Consultation: Understanding the Treatment Plan
After reviewing the course of treatment prior to receiving HITV therapy and laboratory data such as PET-CT, ICVS Tokyo Clinic physicians will assess your current general condition and develop a treatment plan that is most appropriate for you.
Apheresis: Blood Component Separation Method
Apheresis is a procedure in which blood is centrifuged to extract specific blood cells and plasma. It takes 2 to 3 hours to extract mononuclear cells (the source of dendritic cells and activated T cells) and plasma (source of cell culture). Specifically, blood is collected from a vein in one of the upper limbs and then centrifuged within a circulatory circuit. After the necessary mononuclear cells and plasma are extracted, other blood components are returned to the body through the veins of the other upper limb. For this reason, it is necessary to have a relatively large blood vessel. If the veins in the patient's arms have become narrowed due to the use of anticancer drugs, etc., veins or arteries from other parts of the body may be used.
Biopsy: Analysis of inflammatory cytokine expression
Inflammation of the tumor may occur as a rapid immune response to intratumoral administration of Dendritic Cells. Inflammation of the tumor promotes transformation of the cancer cells and increases their proliferative potential, making the suppression of inflammation a critical process in the intratumoral administration of Dendritic Cells.
At ICVS Tokyo Clinic, we know through many clinical experiences that certain cytokines are involved in the inflammation process. Therefore, as an important response to HITV therapy, antibody drugs for inflammatory cytokines can be administered together with Dendritic Cells to suppress inflammatory complications.
As a pre-diagnosis for this purpose, a partial tissue sample (biopsy) is taken from the tumor and analyzed for expressed inflammatory cytokines to select the drugs to be used in the HITV treatment plan.
Cell Culture: Cultivation of Dendritic Cells and Activated T Cells
The components collected through apheresis are immediately transported to our group's CPC (Cell Processing Facility), where cultivation of Dendritic Cells and activated T cells begins. The cultivation period is generally about 4 weeks, although it depends on the condition of the collected components.
In our group, the following facilities have obtained official permission from the Ministry of Health, Labour and Welfare as specified cell processing facilities in accordance with the Regenerative Medicine Safety Ensuring Act.
ICVS Tokyo Clinic Cell Culture Room (Facility number FC3150408)
Medical Corporation Shukokai Hasumi Regenerative Medicine Research Institute Culture Department (Facility number FA3150018)
CELL Bio Lab (Facility number FA3220002)
ICVS Tokyo Clinic V2 Cell Culture Processing Facility (Facility number FC3200103)
Dendritic Cell Administration
Cultured Dendritic Cells are administered into the tumor (or into the major blood vessels feeding the tumor) together with an adjuvant called LCM (patented)*3 that enhances antigen recognition ability, with image confirmation by CT.
In such cases, anti-inflammatory cytokine antibody drugs are used in combination as needed. The administered Dendritic Cells complete antigen recognition (learning information held by the cancer as a foreign substance) in approximately 24 hours.
*3 Adjuvant: An auxiliary agent that enhances the effect of the main ingredient. It plays a role in increasing the effectiveness of vaccines.
Activated T Cell Administration
After 24 to 48 hours from the administration of Dendritic Cells, "activated T cells" are administered intravenously through an intravenous infusion.
Activated T cells enhance the "killer activity" to eliminate cancer cells and immunologically memorize the functions of Dendritic Cells in the body. They are also called "memory cells."
Treatment Evaluation
The effectiveness of treatment is comprehensively determined based on data such as PET-CT image diagnosis and blood tests. Depending on the treatment plan, "CTL apheresis/CTL culture/CTL administration" may be performed after treatment evaluation.
Conditions for HITV Treatment
Indication for HITV Therapy depends on the patient’s prior treatment. If the patient is diagnosed as "applicable" for treatment, there is a greater chance of achieving a complete remission. The basic indications for HITV therapy are listed below.
Indications for HITV therapy
Chemotherapy and radiation therapy always come with the problem of "resistance." Resistance refers to the weakening of the effectiveness of a particular treatment when it is repeated.
As shown in the protocol (page 6), HITV therapy may be used in combination with standard treatment. If standard treatment is untreated, there are more protocols to choose from, and the range of treatment applications is accordingly wider.
preHITV Therapy to Prevent Cancer
Since Protocol C, which is administered after tumor disappearance, is also effective in preventing the development of new lesions, Protocol C has been applied separately from a series of treatment processes to prevent recurrence after surgery, and to cancer prevention programs for healthy individuals. It is now called preHITV Therapy (Preventive Human Initiated Therapeutic Vaccine).
Difference between HITV therapy and preHITV therapy
The initial difference between the two treatments, HITV and preHITV, is the site of administration. In the case of HITV therapy, intratumoral administration is performed to make Dendritic Cells learn cancer information. But as preHITV therapy aims at prevention, Dendritic Cells need to be distributed throughout the body. Therefore, we perform intra-arterial administration for this treatment. Arterial administration is usually done with a catheter, but at our Clinic, as with intra-tumor administration, it is injected percutaneously into the artery with CT confirmation. The major advantage of this procedure is that it causes less damage to the body and significantly reduces treatment and post-treatment rest time. The procedure, which generally requires hospitalization, can be performed as a day trip at our Clinic.
Treatment Duration (case sample)
For Patients who are healthy and want to prevent cancer;
Once every 3 months x 3
Once every 4 months x 3
Once every 6 months (continued)
For Patients in prevention of recurrence after disappearance of cancer in the body;
Once every month x 3
Once every 2 months x 3
Once every 3 months x 3
Once every 4 months x 3
Once every 6 months (continued)
Please note: Dosage intervals and administration site will be determined by the doctor depending on the patient's physical condition.
GREETING FROM DR. KENICHIRO HASUMI
Aiming to be a Beacon of Hope for Cancer Patients
With advances in medical technology, there are many cases where patients can return to society after being diagnosed with cancer. However, it is no exaggeration to say that lifeprolonging treatment is still the mainstream for stage IV and recurrent cancer. My motivation for developing and introducing HITV therapy was to save the lives of such patients with advanced cancer.
It has been almost 20 years since I began administering intratumoral Dendritic Cells. HITV therapy has evolved dramatically since then and is highly effective. Patients who are cured despite being diagnosed with cancer often receive "local treatment" such as surgery and radiation. In fact, there are almost no patients with solid tumors, except for hematologic cancers such as leukemia, who are cured by systemic treatment alone. Our HITV therapy has led "immunotherapy," which is basically a systemic therapy, to work locally.
Essential to HITV therapy is the skill to puncture precisely into the tumor. In principle, it is necessary to be able to puncture all sites (except the brain), since cancer does not choose the site of origin. We have developed this technique through numerous clinical experiences. And it is now possible to introduce Dendritic Cells into tumors regardless of the site.
However, when Dendritic Cells are injected into a tumor alone, the tumor itself may become inflamed, resulting in rapid cancer progression. To prevent this inflammation, radiotherapy and anticancer agents have been used until recently (Protocols A and B). One of the corrective points of this method was that the timing of cell administration was restricted, resulting in frequent administration. To resolve this issue, I developed a new treatment procedure incorporating an antibody drug for inflammation and named it Protocol D. With the advent of Protocol D, it became possible for us to vaccinate tumors without the restrictions of standard treatment. By simplifying the treatment, we were also able to reduce the burden on patients.
I hope that the HITV therapy we have developed and refined will be a beacon of hope for patients with advanced cancer.
Kenichiro Hasumi, M.D.
Chairman, Hasumi International Research Foundation
