The best place where our system learns how to fight cancer is inside the tumor. There are new drugs in immunotherapy that can have powerful effects if they are used correctly. Numerous animals and few human studies have been conducted through injection of some of the FDA-approved immune checkpoint inhibitors, for example, anti-CTLA-4 and anti-PD-1, which show seem to be successful in systemic treatments with immune checkpoint inhibitors, such as Opdivo, Keytruda, and Yervoy. Likewise, the intratumoral injection of these drugs takes the patient much closer to a cure.

The OX40 receptor, also called CD134, is part of the superfamily tumor necrosis factor receptor, this is a co-stimulatory molecule and is expressed on activated and antigen-presenting T-cells. This receptor is the opposite of many of the other immunotherapy agents described above and which are widely used in current treatments, such as anti-PD-1 and anti-CTLA-4.

As described before, these agents block the receptors that are the brakes on the immune system. The OX40 would be equivalent to an “accelerator pedal”. The OX40 has a dual function; it can remove the brakes (regulatory cells) and increase the activation of T-cells (press the accelerator). Unlike traditional immune checkpoint inhibitor therapies used today, by using OX40 we are not blocking the receptor, we are activating it. As is common with most of these immune receptors, you can find them in many places, and they can work differently depending on where they are located. In this case, the OX40 agonist (stimulatory) antibody works in two ways, it stimulates immune activation, but it also binds to regulatory (inhibitory) cells and kills them. A simple way to describe it is that the OX40 agonist releases the brake and presses on the accelerator at the same time.

We are currently treating human patients with multiple types of cancer with the OX40/CpG agonist injected into the tumor. Thus, we have found that, in the case of humans, in order to achieve even better results, we have had to add the CTLA-4 inhibitor called Yervoy.

In immunotherapy, it is not only the correct combination of agents but also the correct sequence that is vital for success. Besides, there are some studies showing that immunotherapy applied in the wrong order, can adversely affect your future potential for a successful immune response. Hence, it is important to highlight that first it is necessary to stimulate the immune system to be attracted to the tumor.

For an effective immune response, the immune system not only needs to recognize cancer but drugs cannot be used systemically throughout the body by oral or intravenous administration. They must be used directly at the site of the tumor.

Furthermore, oncologists are not trained to inject into tumors, but they have the most control over the cancer treatment, and certain drugs injected into tumors will generate less profit than those administered systemically. There is an FDA-approved RTT agonist for topical use called Imiquimod, under the brand name Aldara. It is used for certain types of skin cancer and is being evaluated for topical use for breast cancer as well.

In addition, CpG´s are short single strands of DNA found in large numbers in certain bacteria. The immune system has evolved to recognize them as dangerous, which helps trigger an immune response. This is the main active component in Coley toxins, dead bacteria that Dr. Coley injected into tumors to help stimulate an immune response against cancer more than 100 years ago.

Moreover, the tumor environment does not have enough immune cells present when immune cells are present, we call it a “warm or swollen tumor environment,” which has a better prognosis. When immune cells are not present, we call it a “cold or desert tumor environment,” which has a poor prognosis. You need to have signals that attract immune cells to the tumor. However, this is a bit more complicated than you might think. Immune cells don’t swim toward a tumor. The cells that line the blood vessels must summon them. Since tumors control the local growth of blood vessels, to survive and avoid the immune response tumors build blood vessels that are less likely to attract immune cells, they have vessels that can attract regulatory cells to protect them and destroy effector T-cells (attackers) that want to kill them. Essentially, the tumor controls the pathways in this territory, so it will keep the enemy out. This is another barrier to the immune system.

In addition, CpGs have been shown to help initiate changes in blood vessels, which can then attract the required immune cells.

Finally, there are numerous techniques to stimulate an immune response in a tumor. It has been seen that in some cases the vaccines intended to prevent another disease, could inadvertently stimulate an immune response in cancer.


Williams, J. (2019, 15th October) The Immunotherapy Revolution. (pp. 56-65)