Next-generation ACT

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:

Immatics is actively investigating multiple next-generation strategies to enhance the potency of ACT product candidates to combat solid tumors. For the success of immunotherapies in solid tumors, the complex tumor microenvironment is regarded as one of the biggest challenges. Immatics believes that targeting stroma targets (such as COL6A3 exon 6 in IMA204), as well as Immatics’ next-generation enhancement technologies to generate more potent T cells, may address this unmet need.

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®.

As part of its next-generation strategy Immatics is pursuing a stepwise approach towards highly personalized multi-TCR-T therapy designed to combat target heterogeneity and tumor escape for deeper and longer clinical responses.

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 in an efficient and cost-effective manner.

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.

At the same time we are also committed to enhancing the potency of our ACT product candidates using several next-generation Technologies.

Tumor Stroma

The rigid stroma and the immunosuppressive microenvironment of solid tumors pose a significant challenge for T cell accessibility and activity. Targeting this compartment could provide a novel approach for the treatment of many solid tumors either as single attack or as part of a multi-TCT-T concept. Immatics’ fourth ACTengine® program IMA204 is directed against COL6A3 exon 6, a novel tumor stroma target identified and validated by Immatics’ XPRESIDENT® technology platform. COL6A3 exon 6 is highly expressed in the stroma of a variety of solid tumors. Thus, IMA204 is designed to disrupt the tumor’s protective microenvironment in order to make a therapeutic impact.

Cell Therapy

Current challenges for effective cancer immunotherapies include tumor heterogeneity and tumor immune escape. Immatics aims to combat these limitations and to achieve deeper and longer clinical responses with its next-generation multi-TCR-T approach. To develop this approach, Immatics combines the expertise from the ACTolog® multi-target pilot study with the capability to engineer novel potent TCRs as used in the ACTengine® approach.

Immatics’ ACTolog® pilot trial (IMA-101-101) was the first step towards the implementation of a multi-TCR-T concept and showed clinical feasibility of a personalized multi-target approach against defined cancer targets. The ACTolog® concept is based on selecting and expanding a patient’s own non-engineered T cells dependent on the detection of ACTolog® targets in the patient’s tumor tissue. Results of this clinical pilot study support further exploration of a personalized ACT approach using T cells engineered with potent high-affinity TCRs as in Immatics’ lead product class ACTengine®.

Immatics is planning to take the next steps towards multi-TCR-T immunotherapy through combinatorial treatment of patients using anti-tumor and anti-stroma ACTengine® product candidates (IMA201-204). By attacking different compartments of the tumor and its microenvironment through different target classes, we aim to avoid the tumor escaping from a single cancer target attack.

Immatics further aims to extend the impact of immunotherapy through a novel highly personalized multi-TCR warehouse approach. 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) aiming to deliver the power of T cells to a vast majority of cancer patients. This approach 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.