JP2022520991A - T細胞レパートリーダイナミクス及び腫瘍溶解性ウイルス療法 - Google Patents
T細胞レパートリーダイナミクス及び腫瘍溶解性ウイルス療法 Download PDFInfo
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Abstract
Description
本出願は、2019年2月22日に出願された米国仮特許出願第62/809,190号に基づく優先権を主張するものであり、当該出願の全容を参照によって本明細書に援用するものである。
本明細書では、例えば、全生存期間の改善及び/または無増悪生存期間の改善を示すことによって対象が治療に応答性を有することを示す1つ以上のマーカーを有する対象を選択することによって対象のがんを治療する方法を提供する。本方法は、対象に1回以上の用量の腫瘍溶解性ウイルス(すなわち、腫瘍溶解性ウイルスによる最初のラウンドの治療)を投与することと、1回以上の用量の腫瘍溶解性ウイルスの投与後に高い末梢クローン性を示すT細胞集団を有する対象を選択することと、選択された対象に後続の1回以上の用量の腫瘍溶解性ウイルス(すなわち、腫瘍溶解性ウイルスによる第2のラウンドの治療)を投与することと、を含む。場合により、対象は多様性の低いT細胞集団も有する。末梢クローン性が高くかつ多様性が低いT細胞集団を有する対象を選択することで、選択を行わない対象と比較して、または1回以上の用量の腫瘍溶解性ウイルスの投与後に末梢クローン性が高くかつ多様性が低いT細胞集団を有さない対象と比較して、腫瘍溶解性ウイルスによる後続の治療(すなわち、第2のラウンドの治療)に際して、より長い無増悪生存期間及び/または全生存期間を示す対象が選択される。
レオウイルス血清型3であるDearing株(ペラレオレプ)は、腫瘍溶解ならびに自然免疫応答及び適応免疫応答を誘導し、炎症性の表現型及び抗腫瘍活性をもたらすことが示されている非エンベロープ型のヒトレオウイルスである。第一選択治療後に進行した(治療を忍容しなかった)、進行した(切除不能または転移性の)組織学的に確認された膵臓腺癌の患者に、ペラレオレプ及び化学療法をペムブロリズマブと併用して用いた試験を行った。この研究は、ペムブロリズマブ及び、疾患が進行するまで治療サイクルでこのうちの1つを3週間ごとに反復した3つの化学療法バックボーンレジメンであるゲムシタビン、イリノテカン、またはロイコボリン/5-フルオロウラシル(5-FU)のうちの1つを、ペラレオレプの静脈内投与と併用することを特徴とする。
クローン性及び多様性は、下式を用いて計算した:
T細胞応答及び腫瘍微小環境(TME)内の変化を調べるため、早期乳癌の女性を2つのグループ(各6人の患者)に分け、ペラレオレプをレトロゾールまたはアテゾリズマブと併用して投与した。1、2、8、及び9日目にペラレオレプで患者を治療した。3日目からレトロゾールを毎日投与し、アテゾリズマブは3日目に1回投与した。腫瘍生検を診断時、3日目、及びおよそ21日目に収集した。試験の主要エンドポイントはCelTILスコアとした。CelTILスコアは、腫瘍の細胞性とTILの浸潤の変化を定量化するための指標であり、CelTILの増加は、治療に対する良好な応答と関連している(Nuciforo,et al.,Ann.Oncol.29:170-77(2018))。腫瘍組織をペラレオレプ複製について調べ、TMEへの変化を免疫組織化学及びTCR免疫シークエンシング(免疫SEQアッセイ)によって評価した。末梢血もTCR免疫シークエンシングによって調べた。
Claims (28)
- 対象のがんを治療する方法であって、
(i)1回以上の用量の腫瘍溶解性ウイルスを前記対象に投与することと、
(ii)前記1回以上の用量の前記腫瘍溶解性ウイルスの投与による治療後に高い末梢クローン性を示すT細胞集団を有する対象を選択することと、
(iii)前記高い末梢クローン性を示すT細胞集団を有する対象に、1回以上の後続の用量の前記腫瘍溶解性ウイルスを投与することと、を含む、前記方法。 - 前記末梢クローン性が0.06よりも高い、請求項1に記載の方法。
- 前記対象が、多様性の低いT細胞集団も有する、請求項1または2に記載の方法。
- 前記T細胞集団の多様性が、1800通り未満の再構成である、請求項3に記載の方法。
- 前記がんが、腺癌である、請求項1~4のいずれか1項に記載の方法。
- 前記がんが、乳癌または膵臓腺癌である、請求項1~4のいずれか1項に記載の方法。
- 約103~1012プラーク形成単位(PFU)の前記腫瘍溶解性ウイルスが前記対象に投与される、請求項1~6のいずれか1項に記載の方法。
- 約108~1012PFUの前記腫瘍溶解性ウイルスが前記対象に投与される、請求項1~6のいずれか1項に記載の方法。
- 約108~1012TCID50の前記腫瘍溶解性ウイルスが前記対象に投与される、請求項1~6のいずれか1項に記載の方法。
- 前記腫瘍溶解性ウイルスが、静脈内注入として投与される、請求項1~9のいずれか1項に記載の方法。
- 1つ以上のさらなる治療薬を前記対象に投与することをさらに含む、請求項1~10のいずれか1項に記載の方法。
- 前記さらなる治療薬が、化学療法剤である、請求項11に記載の方法。
- 前記さらなる薬剤が、免疫チェックポイント阻害剤またはアロマターゼ阻害剤である、請求項11に記載の方法。
- 前記免疫チェックポイント阻害剤が、PD-1またはPD-L1阻害剤である、請求項13に記載の方法。
- 前記免疫チェックポイント阻害剤が、ニボルマブ、ラムブロリズマブ、ペムブロリズマブ、アテゾリズマブ、アベルマブ、デュルバルマブ、及びセミプリマブからなる群から選択される、請求項13に記載の方法。
- 末梢クローン性が高くかつ多様性が低いT細胞集団を有する前記対象の選択により、選択を行わない対象と比較して、または1回以上の用量の前記腫瘍溶解性ウイルスの投与後に末梢クローン性が高くかつ多様性が低いT細胞集団を有さない対象と比較して、前記腫瘍溶解性ウイルスで治療した前記対象の無増悪生存期間または全生存期間が長くなる、請求項1~15のいずれか1項に記載の方法。
- 前記腫瘍溶解性ウイルスが、レオウイルス、ニューカッスル病ウイルス(NDV)、小胞性口内炎ウイルス(VSV)、アデノウイルス、ワクシニアウイルス、パラポックスorfウイルス、シンドビスウイルス、及び単純ヘルペスウイルスからなる群から選択される、請求項1~16のいずれか1項に記載の方法。
- 前記レオウイルスが、哺乳動物のレオウイルスである、請求項17に記載の方法。
- 前記レオウイルスが、ヒトレオウイルスである、請求項18に記載の方法。
- 前記レオウイルスが、血清型1のレオウイルス、血清型2のレオウイルス、血清型3のレオウイルスからなる群から選択される、請求項18に記載の方法。
- 前記レオウイルスが、血清型3のレオウイルスである、請求項20に記載の方法。
- 前記血清型3のレオウイルスが、Dearing株のレオウイルスである、請求項21に記載の方法。
- 前記レオウイルスが、IDACアクセッション番号190907-01として寄託されている、請求項18に記載の方法。
- 前記レオウイルスが、1つ以上のアミノ酸改変を有するラムダ3ポリペプチド、1つ以上のアミノ酸改変を有するシグマ3ポリペプチド、1つ以上のアミノ酸改変を有するミュー1ポリペプチド、1つ以上のアミノ酸改変を有するミュー2ポリペプチド、またはそれらの任意の組み合わせを含む、請求項18に記載の方法。
- 前記レオウイルスが、以下のポリペプチド:
1つ以上のアミノ酸改変を有するシグマ3ポリペプチドであって、前記1つ以上のアミノ酸改変が、GenBankアクセッションK02739に対して番号付けした場合に、残基14のLeu、残基198のLys、またはそれらの任意の組み合わせからなる群から選択され、前記アミノ酸配列が残基14にLeuを有する場合、前記アミノ酸配列は、前記アミノ酸配列内に少なくとも1つのさらなる改変をさらに含む、前記シグマ3ポリペプチド;
少なくとも1つのアミノ酸改変を有するミュー1ポリペプチドであって、前記少なくとも1つのアミノ酸改変が、GenBankアクセッション番号M20161.1に対して番号付けした場合に残基73のAspを含む、前記ミュー1ポリペプチド;
1つ以上のアミノ酸改変を有するラムダ3ポリペプチドであって、前記1つ以上のアミノ酸改変が、GenBankアクセッション番号M24734.1に対して番号付けした場合に、残基214のVal、残基267のAla、残基557のThr、残基755のLys、残基756のMet、残基926のPro、残基963のPro、残基979のLeu、残基1045のArg、残基1071のVal、またはそれらの任意の組み合わせからなる群から選択され、前記アミノ酸配列が残基214にVal、または残基1071にValを有する場合、前記アミノ酸配列は、前記アミノ酸配列内に少なくとも1つのさらなる改変をさらに含む、前記ラムダ3ポリペプチド;または
少なくとも1つのアミノ酸改変を有するミュー2ポリペプチドであって、前記少なくとも1つのアミノ酸改変が、GenBankアクセッション番号AF461684.1に対して番号付けした場合に残基528のSerを含む、前記ミュー2ポリペプチドのうちの1つ以上を含む、請求項18に記載の方法。 - 前記レオウイルスが、以下のゲノムセグメント:
1つ以上の核酸改変を有するS4ゲノムセグメントであって、前記S4ゲノムセグメント内の前記1つ以上の核酸改変が、GenBankアクセッション番号K02739に対して番号付けした場合に74位のA及び624位のAからなる群から選択される、前記S4ゲノムセグメント;
少なくとも1つの核酸改変を有するM2ゲノムセグメントであって、前記少なくとも1つの核酸改変が、GenBankアクセッション番号M20161.1に対して番号付けした場合に248位のCを含む、前記M2ゲノムセグメント;
1つ以上の核酸改変を有するL1ゲノムセグメントであって、前記1つ以上の核酸改変が、GenBankアクセッション番号M24734.1に対して番号付けした場合に660位のT、817位のG、1687位のA、2283位のG、2284~2286位のATG、2794位のC、2905位のC、2953位のC、3153位のA、3231位のGからなる群から選択される、前記L1ゲノムセグメント;または
少なくとも1つの核酸改変を有するM1ゲノムセグメントであって、前記少なくとも1つの核酸改変が、GenBankアクセッション番号AF461684.1に対して番号付けした場合に1595位のTを含む、前記M1ゲノムセグメントのうちの1つ以上を含む、請求項18に記載の方法。 - 前記レオウイルスが、組換えレオウイルスである、請求項18に記載の方法。
- 前記レオウイルスが、改変レオウイルスである、請求項18に記載の方法。
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- 2020-02-21 CA CA3129036A patent/CA3129036A1/en active Pending
- 2020-02-21 WO PCT/IB2020/051493 patent/WO2020170215A1/en unknown
- 2020-02-21 JP JP2021549080A patent/JP2022520991A/ja active Pending
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EP3927359A4 (en) | 2023-01-25 |
SG11202108680XA (en) | 2021-09-29 |
CA3129036A1 (en) | 2020-08-27 |
AU2020225917A1 (en) | 2021-08-26 |
KR20210130760A (ko) | 2021-11-01 |
CN113825522A (zh) | 2021-12-21 |
MX2021009907A (es) | 2021-09-14 |
WO2020170215A1 (en) | 2020-08-27 |
IL285636A (en) | 2021-09-30 |
EP3927359A1 (en) | 2021-12-29 |
US20220105143A1 (en) | 2022-04-07 |
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