Adoptive Cell Therapy
Immatics is developing Adoptive Cell Therapies, which are designed to leverage the power of T cells to actively infiltrate tumor tissue and kill tumor cells in a specific and serial fashion.
Immatics’ clinical ACTengine® program is a personalized approach in which the patient’s own T cells are genetically modified to express a novel proprietary TCR cognate to one of Immatics’ proprietary cancer targets and are then reinfused. This approach is also known as TCR-T (T cell receptor T cell). The ACTallo® program is advancing the ACT concept beyond individualized manufacturing and is being developed to generate “off-the-shelf” cellular therapy. The ACTolog® program is a pilot approach for ultra-personalized, multi-target immunotherapy utilizing endogenous (non-genetically engineered) T cells with the goal of paving the way for a next step of enabling a fully engineered multi-TCR-T.
ACTengine® at a glance
- Expanded target space compared to CAR-T. ACTengine® TCR-T targets tumor-associated peptides presented by HLA-molecules on the tumor cell surface. Most relevant solid cancer targets are of intracellular nature and thus only accessible by TCR-based approaches.
- TCRs with desirable affinity and specificity. ACTengine® TCRs identified via the XCEPTOR™ TCR discovery and characterized via XPRESIDENT® guided on- and off-target toxicity screening show desirable affinity and high specificity. Immatics’ competitive advantage to other TCR-T approaches is the combination of the most suitable target (via XPRESIDENT®) with the right TCR (via XCEPTOR™).
- Active at physiological levels of target expression. Immatics believes that ACTengine® TCR-T products are highly potent and capable of inducing the killing of tumor cells presenting physiological target copy numbers identified by quantitative mass spectrometry and TCR validation.
- Optimized manufacturing. Immatics’ proprietary short manufacturing process including a significantly shorter manufacturing period and a proprietary cytokine cocktail used to promote T cell expansion in culture is designed to produce younger, less differentiated T cell phenotypes which are associated with better engraftment and in vivo persistence.
- Patient recruitment. Patient recruitment is underway in three first-in-human clinical trials. The clinical trials are investigating safety, tolerability and initial signs of efficacy in patients and are designed to include potential expansion cohorts in the case of initial signs of clinical efficacy. This may enable a fast way forward towards pivotal clinical trials in specific indications.
- Early biological data from first patients treated. Initial biological data from the first patients treated in the ACTengine® trials (N=4) suggest a high persistence of target-specific T cells after infusion, already at the first low-dose level, which constitutes approximately 5-10% of Immatics’ anticipated target dose. These target-specific T cells can also be detected in post-treatment tumor biopsies.
There are several reasons why a patient’s own T cells are often not able to protect the body against cancer, such as unavailability of activated tumor antigen specific T cells or insufficient affinity of endogenous target specific TCRs to properly activate the T cell and fight the tumor. Immatics believes that these problems can be overcome by engineering of autologous T cells with a well characterized and potent TCR, an approach used in its ACTengine® program.
ACTengine® is based on genetically engineering a patient’s own T cells with a novel TCR designed to recognize the cancer target identified by Immatics’ XPRESIDENT® platform. If the target of interest is confirmed on a patient’s tumor by the IMADetect™ companion diagnostic device candidate, lentiviral transduction of the patient’s autologous T cells with a target specific exogenous TCR essentially “reprograms” the T cells to attack the tumor. The engineered T cells are then multiplied in vitro and reinfused back into the patient to treat the tumor.
In Immatics’ current ACTengine® clinical trials, infusion of the engineered T cells is preceded by a preconditioning lymphodepleting chemotherapy to activate proliferation, facilitate T cell engrafting and persistence. Post-infusion of the T cell product, low-dose IL-2 is administered for 14 days to further enhance persistence of the adoptively transferred cells.
Next-Generation ACT at a glance
Immatics is committed to developing its ACTengine® programs with the goal of delivering the potential benefits of its innovative science to cancer patients as soon as possible. At the same time, in order to achieve the best outcomes for cancer patients in the longer term, Immatics strives to enhance the tolerability, potency and ease of use of its product candidates. To accomplish these goals, Immatics has taken the following steps:
- Addressing the tumor stroma and microenvironment. The complex tumor microenvironment is currently regarded as one of the biggest challenges to the success of immunotherapies in solid tumors. Immatics believes that the combination of stroma targets with tumor targets, as well as Immatics’ second-generation enhancements to generate more potent T cells, may address this unmet need.
- Combating target heterogeneity and tumor evasion. Immatics’ next generation multi-target approach is designed to combat target heterogeneity and tumor escape for deeper and longer clinical responses.
- Enhancing commercial viability. Aside from improving commercially compatible manufacturing of autologous ACT, Immatics aims to decrease the cost of goods and to reach patients more quickly with its off-the-shelf cell therapy, ACTallo®.
- Pioneering personalized multi-target precision cancer medicines. The ACTolog® pilot trial served as the first proof-of-concept for the feasibility of a personalized multi-target approach. The ACTolog® pilot trial indicated a favorable tolerability profile, persistence and biological activity of transfused T cells as well as clinical benefit by the long-term stabilization of tumor growth in some last-line patients. The ACTolog® approach is limited by the properties of the patient’s own T cell repertoire (i.e. TCRs with limited affinities). Immatics believes that this limitation can be overcome by a multi-TCR-based ACTengine approach, which utilizes highly potent and optimized TCRs that may enable significant clinical responses.
- Exploit the full target potential and offer treatment options for potentially any patient. Immatics believes that its pool of more than 200 prioritized targets combined with the capability to develop the right TCRs offers a possibly unique foundation to develop treatments for almost any patient. Immatics believes that its fast manufacturing process, combined with its broad target portfolio, may put it in a unique position to develop personalized medication efficiently and cost-effectively for any patient.
ACTallo® - Off-the-shelf Adoptive Cell Therapy
ACTallo® is a process developed by Immatics for the manufacture of allogeneic, off-the-shelf, TCR-engineered cellular therapies derived from healthy donors’ gamma delta T cells.
Immatics believes that gamma delta T cells are ideally suited for allogenic Adoptive Cell Therapy approaches because:
- gamma delta T cells naturally infiltrate tumors
- infiltration by gamma delta T cells has been shown to be the most favorable prognostic factor for patient outcome
- gamma delta T cells possess intrinsic antitumor activity and recognize target cells in an HLA/peptide independent fashion, not causing Graft-versus-Host Disease
Immatics has developed a process that allows ex vivo expansion of gamma delta T cells isolated from a single healthy donor to manufacture many ACTallo® doses, which Immatics believes represents an ideal modality for an off-the-shelf approach. Using healthy donor T cells circumvents the need to use T cells from heavily treated or aging cancer patients, thus allogeneic cells are not encumbered by suppressive environments of the patients´ immune system. In addition, products are available immediately for patient treatment without any delays for cellular manufacturing upon enrollment. At the laboratory scale, Immatics has observed that its proprietary manufacturing process could generate hundreds of doses from a single donor. Immatics is currently translating these lessons into larger scale solutions.
ACTolog® - Multi-target cell therapy pilot trial
The ACTolog® approach was designed as the first known multi-target precision immunotherapy. The IMA101-101 first-in-human clinical trial is currently being conducted as a pilot trial to demonstrate safety and feasibility of a multi-target ACT approach.
ACTolog® is based on the principle of endogenous T cell therapy pioneered by Cassian Yee.
ACTolog® T cells are not genetically modified: IMA101 T cell products are generated from peripheral blood cells and are the patient’s own T cells, which are applied after ex vivo expansion.
This approach by Cassian Yee is based on the observation that tumor antigen-specific T cells are naturally occurring and can be identified in the peripheral blood of melanoma patients. Despite their natural ability to recognize tumor associated antigens that are presented by tumor cells, these T cells may not become activated and capable to act against cancer, as peptides presented without co-stimulatory signals are only poorly immunogenic. Moreover, their frequency is usually very low. Expanding and activating those naturally occurring T cells allows great flexibility in targeting tumors.
In ACTolog®, this autologous T cell expansion approach is amended to use a warehouse including multiple novel cancer targets discovered by Immatics’ target discovery platform XPRESIDENT®. From this target pool, the most suitable targets for each patient’s tumor are identified by analyzing their relative presence within a tumor biopsy. Up to four personalized ACTolog® T cell products, each with a defined target specificity, are then manufactured for each patient by isolation, propagation and activation of the patient’s endogenous T cells in vitro. Billions of such activated and specific T cells are then re-infused into the cancer patient to fight the tumor. The patient-tailored IMA101 T cell product(s) are infused as single dose after a pre-conditioning lymphodepletion to facilitate engraftment of transferred T cells. Thereafter, patients receive low-dose IL-2 to further improve T cell engraftment and activation.
The ACTolog® pilot trial served as the first proof-of-concept for the feasibility of a personalized multi-target approach. The ACTolog® approach is limited by the properties of the patient’s own T cell repertoire (i.e. TCRs with limited affinities). Immatics believes that this limitation can be overcome by a multi-TCR-based ACTengine® approach, which utilizes highly potent and optimized TCRs that may enable significant clinical responses.
Personalized multi-target ACTengine® and TCR warehouse
With the XPRESIDENT® target discovery platform, Immatics is not only able to identify tumor cell-associated targets, but also innovative targets that are predominantly expressed in tumor stroma. One such stroma-associated target is COL6A3 exon 6, which was selected for the IMA204 ACTengine® program. Immatics believes that targeting the tumor stroma via IMA204 ACTengine® is a promising approach for many solid tumors. This could result in tumor cell death due to tumor cells’ dependency on the stroma, could allow endogenous tumor specific T cells to reach the tumor and exert their anti-tumor activity, or could trigger additional local inflammation in the tumor microenvironment
Immatics further aims to extend the impact of immunotherapy through a novel ultra-personalized multi-TCR warehouse approach.
To achieve this, Immatics combines the expertise from the ACTolog® multi-target pilot study with the capability to develop novel engineered TCRs as used in the ACTengine® approach. While developing ACTengine® targets individually, Immatics will take the first step towards multi-TCR-T immunotherapy through combinatorial treatment of patients using anti-tumor and anti-stroma ACTengine® products (IMA201-204). This will enable attacking different compartments of the tumor and its microenvironment through different target classes, thereby aiming to avoid the tumor adjusting to and escaping from a single cancer target attack.
With a portfolio of >200 prioritized cancer targets and the high-throughput capabilities in TCR discovery and characterization, Immatics is well-positioned to build a broad library of TCR product candidates (TCR warehouse) aimed at delivering a pioneering, ultra-personalized cancer treatment. A treatment algorithm to select and deliver multiple TCR-based cell therapy products for any cancer patient will not only expand the treatable patient population, but is designed to ultimately reduce the likelihood for tumors to evade immunotherapy and prolong durability of clinical responses, possibly even resulting in cure.